National Academies Press: OpenBook

Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects (1983)

Chapter:6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES

« Previous: 5 EFFECTIVE BIOLOGIC DOSE
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page273
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page274
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page275
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page276
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page277
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page278
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page279
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page280
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page281
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page282
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page283
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page284
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page285
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page286
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page287
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page288
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page289
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page290
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page291
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page292
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page293
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page294
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page295
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page296
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page297
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page298
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page299
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page300
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page301
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page302
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page303
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page304
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page305
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page306
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page307
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page308
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page309
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page310
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page311
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page312
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page313
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page314
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page315
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page316
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page317
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page318
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page319
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page320
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page321
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page322
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page323
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page324
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page325
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page326
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page327
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page328
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page329
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page330
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page331
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page332
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page333
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page334
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page335
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page336
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page337
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page338
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page339
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page340
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page341
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page342
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page343
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page344
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page345
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page346
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page347
Suggested Citation:"6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES." National Research Council. 1983. Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects. Washington, DC: The National Academies Press. doi: 10.17226/738.
×
Page348

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

CIRCULATORY SYSTEM Juchau et al .76~77 summarized a body of literature bearing on the hypothesis that PAHs may play an important role in the pathogenesis of arteriosclerotic lesions. The validity of this hypothesis apart, these investigators clearly demonstrated that aortic tissues from a number of species, including man, have detectable, albeit low, monooxygenase activities using BaP and 7,12-DMBA as substrates. Enzyme activities were comparable with those characterizing mouse skin. Cytochrome P-450 could be detected in primate aortas, and epoxide hydratase activity for BaP 4,5-oxide was identified in homogenates of the arterial walls of chickens and rabbits. The characteristics of the aortic monooxygenase for BaP resembled those of the enzyme system found in other tissues. It could be markedly induced, for example, by 3-MC, polychlorinated biphenyls (PCBs), and 5,6-benzoflavone; and, surprisingly, aortic homogenates produced higher than expected quantities (by as much as a factor of 28) of alkali-extractable metabolites when hematin was added to the reaction mixtures. Interestingly, hematin has been shown in other studies to degrade, in vitro, components of the monooxygenase system.lll The primary BaP metabolites formed in rabbit aortic homogenates were the 3-OH and 9-OH derivatives, phenolic compounds known to be cytotoxic. The authors cited unpublished data to show that the aortic metabolites of BaP form covalent bonds with such macro- molecules as calf-thymus DNA. Treatment of chickens with the inducer 3-MC markedly increased the amount of the PAM-DNA adducts, whereas addition of 7,8-benzoflavone in vitro inhibited binding. Aortic enzymes also have been shown to catalyze the formation of mutagenic metabolites from 7,12-DMBA. Thus, both cytotoxic and mutagenic metabolites of PAHs can be generated in vascular tissues. The possible relation of the formation of these compounds to the initial vascular injury that may presage the local development of an atherosclerotic plaque is of considerable interest. The interaction of benz~aJanthracene and BaP with crystalline human serym albumin in solution has been studied fluorimetrically by Ma et al. 10 Equilibrium studies indicated that both PAHs hind to the pro- tein to the same extent. Evidence of energy transfer from the trypto- phan residue of the protein (increase in the weak B region--395-420 nm--fluorescence of the PAHs) permitted an assessment of the mean dis- tance between the tryptophan and the bound ligand, thus identifying two different binding sites in the same general area. The authors sug- gested that structural differences among hydrocarbons, which may greatly affect their orientations on the protein molecule, influence mainly the selection of the binding site, rather than the binding equilibrium. In vivo BaP associates very little with serum albumin in the presence of lipoproteins. The kinetics of BaP transfer between human plasma lipoproteins have been examined by Smith and Doodyl63 with high-density lipoproteins (HOL), low-density lipoproteins (LDL), and 6-ll

very-low-density lipoproteins (VLDL) prepared from fresh unfrozen human plasma by ultracentrifugal flotation. BaP-lipoprotein interactions were analyzed fluorimetrically, and kinetic measurements were determined by stopped-flow techniques. The half-times of BaP transfer between HDLs, between LDLs, and between VLDLs were 40, 180, and 390 ms, respectively. The transfer of these PAHs among lipoproteins of the same density class was about one-twentieth that of pyrene under the same conditions. The rate of BaP transfer between lipoproteins also decreased with increasing size of lipoprotein; at equilibrium in vitro, VLDLs contain about 10 times more of the BaP than LDLs, and LDLs contain 20-50 times more than HDLs. The distribution between plasma and erythrocytes is different for 7,12-DMBA, BaP, benzanthracene, and anthracene, the mass of the PAH being associated with red cells (50, 70, 93, and 100t, respectively). Plasma lipid concentrations and the dynamics of lipid and lipoprotein metabolism clearly may have an impact on PAH distribution in blood and into specific tissues. For example, transfer of BaP is quite rapid, compared with the half-time for either hydrolysis of chylomicron triglyceride (about 2-5 min in humans) or clearance of the most abundant lipoproteins from the circulation (3-5 d in humans). The data of Smith and Doodyl63 concerning the role of plasma lipoprotins in the transport of PAHs corroborated and extended the findings of other invle~t~ai2ors wh6O examined the interaction of PAHs and plasma proteins. , , ,57,1 2 The specific process of BaP uptake from human LDLs into cultured human cells was examined by Remsen and Shireman.149 The cell lines used were WI-38, a human embryonic lung-fibroblast line, and GM 1915, a skin-fibroblast line derived from a patient with homozygous familial hypercholesterolemia; the former cells are LDL-receptor-positive, and the latter LDL-receptor-negative. Thus, in these studies, it was possible to explore the role of LDL receptors in the cellular uptake of PAHs that enter the bloodstream transported by chylomicrons and plasma lipoproteins. The results indicated that cellular uptake of the tritiated PAH by both cell lines from delipidated or serum-free medium varied linearly with concentration, whereas incorporation of PAH bound to LDLs was much less and, at higher lipoprotein concentrations, varied nonlinearly. The prese2ce of the PAH in the LDL preparation did not affect the binding of 1 5I-labe]ed lipoprotein to receptor-positive cells. The study provided several findings of special importance relative to the biologic impact of PAHs--or at least BaP as a model compound--on tissues in vivo. Clearly, although LDLs carry substantial amounts of PAH, the presence of LDL receptors on cel Is is not necessary for tissue uptake. The fact that PAH bound to LDL was incorporated into cells more slowly than PAH in a delipidated serum or serum-free medium raises questions about the biologic significance of experimental models in which increased incorporation of BaP from particles into lipid vesicles has been demonstrated. The data £rom these experiments also indicate that cells that may be directly exposed to a PAH (i.e., tracheobronchial, intestinal, and cutaneous cells) before the compound reaches the bloodstream may accumulate PAH in much higher concentrations than cells exposed to the PAH bound to lipoproteins, inasmuch as the latter significantly slowed as well as limited the 6-12 . -

cellular uptake of BaP. Finally, the report indicated that BaP previously incorporated into WI-38 cells could be substantially removed (by 55-797) in a 120-min posttreatment study period by 10% delipida ted serum or LDL-containing medium. This finding implies a potential for considerable PAN redistribution and a requirement for a not insignificant period for progression of the hydrocarbon from the plasma membrane to the endoplasmic reticulum, where metabolism takes place. The ability of human monocytes to oxidize BaP and the induction of this enzyme activity by bt~z9agth:gcene have been demonstrated by several investigators. 6, , ,1 Lake and colleagues96 re-examined this problem with the goal of developing a practical assay for measuring whole-cell metabolism of BaP under highly standardized conditions, eliminating--among other problems--the need for a large volume of blood (50 ml) in the fluorometric assay developed earlier for AHH activitity in this cell type. By measuring whole-cell generation if water-soluble BaP metabolites over a 3-d culture period, using H-labeled substrate and closely controlling other character- istics, they provided a useful alternative cell system to that using mitogen-stimulated lymphocytes for characterizing BaP oxidation activity in humans. Because of the advantage gained by the much greater inducibility of AHH activity (-up to 40-fold) in cultured monocytes, compared with mitogen-stimulated 1 ~hocytes (about 5-fold), the monocyte system was used by Okuda et al. to study the contribution of genetic factors to the control of individual variation in AHH inducibility. Ten sets of monozygotic tissues were assayed two to four times and 17 sets of dizygotic tissues one to three times for basal and induced monocyte AHH activity. The results indicated that 55-70% of the individual variation in AHH inducibility of monocytes was genetically determined. Variation in AHH inducibility within subjects in repeat assays was wide and approached the magnitude of the variation between subjects. Thus, a single AHH assay is an imprecise biochemical characterization of a subject. Alternatively expressed, the method then available (late 1977) made it impractical to characterize a population with genetically distinct differences in AHH inducibility. The large intrasubject variation in AHH inducibility of monocytes also indicated that, in addition to the clear genetic influences on this process, unknown environmental or technical factors expressed themselves in the test procedure. An abundant literature exists related to the monooxygenase activity of lymphocytes; the inducibility of this activity by mitogens, which have the property of stimulating lymphocyte transformation, during which a number of metabolic activities are concurrently greatly increased; and the use of mitogen-stimulated lymphocytes to study the genetic control of AHH in man and its relation to the occurrence of Some human cancers--notably those of the l~lg,2 Kouri and colleagues have1 revi2ewed key aspects of this subject; ' McLemore et al. 19-12 have also provided a detailed analysis of the genetics of AHH and its purported relation to human cancer. Only a brief summary of these findings can be included here. 6-13

The identification of AHH activity in lymphocytes in 197229,192 and its increase during lymphocyte blastogenesis led quickly to clinical studies, the earliest being that of Kellermann et al. ,87 in which this induced enzyme activity was measured in cultured lymphocytes of normal controls, non-lung-tumor controls, and lung-cancer patients. In a preceding study in the same year, this grouped had examined the genetic variation in AHH activity in lymphocytes of 353 normal subjects and had categorized the population into three groups--low, inter- mediate, and high responders with respect to AHH inducibility; the population frequencies were about 50t, /~0X, and 10%, respectively. The conclusion was reached that the enzyme activity was controlled by two alleles at a single gene locus and that the high and low responders were homozygous and the intermediate group ~7eterozygous for those alleles. In the initial lung-cancer study, there was a virtual absence of cases in the low-inducibility population, and all but two cases were in the intermediate- and high-inducibility categories. All the lung-cancer cases were in heavy smokers; of the 50 subjects, 48 had an average consumption of two packs of cigarettes per day. When the two control groups (normal subjects and a non-lung-cancer tumor group) and the lung-cancer group were compared for risk of lung cancer, those with intermediate and high inducibility (48 of the 50 lung-cancer cases) had risks for lung cancer 16 and 36 times, respectively, the risk in the low-inducibility group. This study prompted considerable controversy over the next few years, during which the findings of Kellermann and associates were cast in doubt. 85 strong correlation (r = 0. 923) was also found by Kellermann et al. between the plasma elimination rate of antipyrine and the rate of BaP metabolism in human lymphocytes from a "carefully selected homogeneous" population, compared with the much lower correlation (r = 0.425) found in a "heterogeneous" population. The authors interpreted their findings as supporting the existence of common oxidative systems or common genetic control of the systems for antipyrine and BaP oxidation. Atlas et al. confirmed that plasma antipyrine half-life is correlated to some extent with AHH inducibility (r = 0.84), although no intrasubject correlations were found between AHH inducibility and the oxidation of other drug substrates, such as phenylbutezone and bishydroxycoumarin. Most importantly, this group, 7 while affirming a significant heritable determinant of AHH inducibility in human lymphocytes, failed to confirm the monogenic model and trimodal distri- bution of AHH indu86bility in the general population, proposed by Kellermann _ al.; rather, the population distributions for AHH inducibility (and for plasma antipyrine half-life) were consistent with polygenic control of both traits in man. In other studies in which the relation of AHH indu-cibility t~ th~ occurrence of lung cancer was re-examined by Paigen et al., 331 4 low AHH activity was found in half the tumor patients studied, in contrast with the earlier findings of Kellermann et al.,87 and no characteristic alterations in this enzyme activity were found in the progeny of these patients. A con- siderable number of technical problems related to the lymphocyte-AHH assay may confound the results obtained in studies of this enzyme 6-14 . . .

activity and its relation to human cancer, as noted by Kouri et al.91 However, recent methodologic advances made by this group, particularly the use of cryopreserved lymphocytes and close control of a number of assay variables, have added an important degree of precision to the assay. Chrysene, one of several PAR derivatives (benzanthracene is another), has been shown by Snodgrass et al.164 to induce AHH activity in cultured human lymphocytes (from normal subjects) with BaP as substrate. The individual variation in the monooxygenase activity observed with other inducers was also seen with chrysene. The comparative metabolism of BaP in human lymphocytes and human liver microsomes has been studied by Selkirk et al.,l6u who examined the nature of the metabolites formed by each cellular system. The patterns of metabolizes formed in both cell systems had characteristics quite similar to each other, with some exceptions--for example, among the derivatives formed in a 30-min incubation, all three dihydrodiols produced by liver were absent in the lymphocyte incubation mixture. In a~24-h incubation of lymphocytes, however, all three dihydrodiols formed by liver microsomes were also formed by the blood cells, and new metabolite peaks were observed, presumably reflecting more extensive biotransformation of already formed metabolizes in the reaction mixture. The authors concluded that, although the ratios of some metabolites may differ and although lymphocytes form several more derivatives than does liver, many identical metabolizes are produced in these two human cell types. Schonwald et al.l58 studied the effect of BaP on sister chromatic exchange in mitogen-stimulated lymphocytes of 11 normal subjects and 18 patients with lung cancer. Patients and controls differed neither with respect to the spontaneous rate of sister chromatic exchange nor in their responses to the hydrocarbon, although it did double the number of exchanges in both population groups. Barfknecht et al.l5 studied the ability of dichloromethane extracts of automobile diesel soot at high concentrations (100 mg/m3) to induce trifluorothymidine-resistant mutants in human lymphocytes incubated in the presence of rat-liver postmitochondrial supernatant. A significant induction of such mutants was observed. Anthracene, phenanthrene, and their alkylated derivatives accounted for one-fourth of the observed biologic activity. Among eight related compounds, there was general agreement between responses in lymphoblasts and in bacterial test systems. Phenanthrene was an exception, in that it was positive in the human-lymphoblast test system, but negative in bacteria at a concentration 60 times higher. The data in this report indicate that methyl substitution at some sites of anthracene and phenanthrene greatly increases their mutagenicity in both S. typhimurium and human lymphoblasts. A similar effect for chrysene has been observed. Methylations at the 1 and 3 positions of phenanthrene and the 2 and 9 positions of anthracene result in PAHs that are particularly mutagenic 6-15 At;

in the human and bacterial test systems used. Methylations at other positions had the capability of eliminating the mutagenic activity of the PAH derivative. No correlation between the results of the mutagenesis studies with the soot-derived PAHs and the reported capacity of the compounds studied to elicit neoplastic or carcinogenic responses in test animals could be made. REPRODUCTION The title of this section refers collectively to studies related to the ability of some genital tissues (including the placenta) to metabolize or otherwise respond biochemically to Part. There is an abundant and detailed literature on transplacental and peri- natall8 carcinogenesis. These and related topics in reproduction were reviewed in a 1981 special issue of the Journal of Environmental Pathology_and Toxicology and are not summarized here. It is perhaps appropriate, however, to refer to the report by Sir Percival Pott in 1775, 42 in which there was first described an increased incidence of scrotal cancer in chimney sweeps exposed to soot and to note that almost 150 yr elapsed before Yamagiwa and Ichikawal§4 demonstrated that the repetitive application of crude coal tar to the rabbit ear produced skin cancer and that the identification of specific carcinogenic coal-tar constituents, such as BaP, required the passage of additional decades.20~43' 8 Over this period, the question of why only scrotal cancers, and not other genital cancers or even other cancers in general, were found in-excess in chimney sweeps appears to - have remained unanswered. Grover _ al.66 investigated the metabolism--including the Specific identification of biotransformation products--of three H-labeled PAHs by nonneoplastic human mammary epithelial-cell aggregates maintained in culture. The lobuloalveolar units from which these aggregates are derived are thought to be the site of origin of many human mammary carcinomas; two of the PAHs studied, 7,12-DMBA and BaP, are known to be relatively potent mammary carcinogens in rats, whereas benz~aJanthracene is not a mammary carcinogen in rats. Tissues from eight patients were studied. The extent of metabolism of the PAHs is summarized in Table 6-4. There was considerable individual variation in PAH metabolism among the subjects studied, but the formation of water-soluble metabolites by the tissue samples accounted, in each instance, for a major portion of the total of each PAH metabolized. The extent of binding of each PAH to cellular DNA and proteins also varied considerably. Interestingly, the extent to which H-labeled metabolites of benz~aJanthracene--a noncarcinogen for mammary tissue in the rat--were bound seemed, from the limited data obtained, to be consistently lower than the binding displayed by the other two PAHs. The results of chromatographic characterization of PAM-DNA adducts formed suggested that, with Hap, the hydrocarbon was activated by the cultured cells through the formation of anti-BaP 7,8-diol-9, 10-oxide, a bay-region diol-epoxide that appears to be responsible for most of the nucleic acid adducts formed in several 6-16

other biologic systems. The situation was less clear with 7,12-DMBA, although a portion of the adducts formed with this PAH cochromatographed with adducts present in a DNA hydrolysate that had been treated with anti-7,12-DMBA 3,4-diol-1,2-oxide--a derivative that is also classified as ~ bay-region diol-epoxide. The authors interpreted their data with caution, considering all the factors known to bear on the development of mammary cancer; but the possibility of partial causal relationships among the PAHs, their metabolic transformations, and tumor stimulation is implicit in this work. Stampfer and colleagues168 did similar studies with BaP and cultured mammary epithelial cells and fibroblasts. They showed that the breast epithelial cells were 50-100 times more sensitive (growth inhibition) to BaP than the fibroblasts; that the epithelial cells formed adducts as early as 6 h after addition of the PAH to the cultures; and that the adducts between the 7R anti stereoisomer of BaP diol-epoxide and deoxyguanosine predominated at all times and, with two minor adducts that were consistently present, persisted in the epithelial cells for at least 72 h in a BaP-free medium. No adducts were detected in fibroblasts until 96 h after exposure to the PAH, at which time the type and extent of adduct formation were similar to those observed with epithelial cells. As with the report of Grover et al.,66 caution concerning the direct relation of these findings to the role of PAHs in mammary carcinogenesis is necessary. On this matter, Stampfer and co-workers168 stated, however, that "chemical carcinogens, particularly BaP, should not be minimized as possible factors in the initiation of breast cancer." Mass et al.113 studied 26 specimens of normal human endometrium _ _ ~ to determine the patterns of metabolism of [~H]BaP in short-term explant cultures. Three of the tissue samples were from postmenopausal women; of the remaining 23, it was possible to approximate the stage of the menstrual cycle at which the tissue was removed during surgery. Eight of the latter subjects were smokers. In summary, it was clear that normal human endometrium could enzymatically convert BaP to a wide variety of oxygenated derivatives that cochromatographed with dihydrodiols, quinones, and monohydroxy products of the PAH; sulfation was also identified. HPLC analysis of metabolites revealed marked individual variation in metabolite formation among the subjects studied; smoking did not account for this difference, but some evidence of hormonal influences on the patterns of PAH metabolism was adduced. In a study by Dorman et al.,52 BaP binding to DNA in human endometrial tissue was studied in samples obtained from 41 subjects and, again, a striking (70-fold) range in the observed specific activities of carcinogen binding to UNA was identified (see Figure 6-1~. Tissues obtained late in the proliferative phase or early in the secretory phase of the menstrual cycle had the highest mean specific activity of PAM-DNA binding (Table 6-5~. Binding was significantly reduced when tissue specimens from low-estrogen periods of the menstrual cycle were studied. The reason for this apparent association between estrogen content (actually, the estimated phase of the cycle) 6-17 ~.. . ..

and PAM-DNA binding is obscure, but clearly merits further study. Such study would have to deal with the important confounding factor of the broad range of individual variation in binding, which may mask systematic but small changes that can occur during a menstrual cycle, but which cannot now be detected. Namkung and Juchaul28 studied the oxidative biotransformation of BaP in preparations of human placental microsomes with HPLC. The investigations revealed that the use of substrate concentrations high enough to ensure zero-order reaction kinetics markedly inhibited the formation of dihydrodiols in the reaction mixtures. The relative quantities of dihydrodiols generated increased with decreasing substrate concentrations between 200 and 2.7 ~M. Addition of manganese or ferric ions to reaction mixtures altered the ratios of generated phenols to dihydrodiols. Identical results were obtained with C- and 3H-labeled BaP as substrate. The data suggested that considerable amounts of 7,8-dibydroxy-7,8-dibydro-BaP, a proximate mutagen-carcinogen, may be generated in vivo by placental tissues of women who smoke. The formation of PAH metabolite-nucleoside adducts when human tumor placental microsomes were incubated with i3H]BaP and salmon sperm DNA has been studied by Pelkonen and Saarni.L 9 There were significant differences between the PAH metabolite patterns and the nucleoside- metabolite complexes formed, compared with rat liver, for example. Specifically, in the human placenta microsomes, the absence of the nucleoside complex of 9-'nydroxy-4,5-oxide implied the inability of this tissue to form 4,5-oxides of BaP. Indirect evidence of epoxide hydratase activity in placental tissue was obtained. The extent of PAM-DNA binding in this tissue correlated significantly with both 7,8-diol metabolite formation and fluorometrically determined AHH activity. The question of whether the 7,8-dioi-9,10-epoxide of BaP is formed by the human placenta in vivo could not be answered unequi- vocally, but the authors' inferential conclusion is that it is probably formed in the human host. The interplay of possible genetic influences and clearly established regulatory influences of environmental factors on Herman placental AHH has been incisively discussed by the same group.l38 Cigarette-smoking has been shown by Conney and associates42~189~190 to be one of the most potent and consistent inducers of human placental AHH activity yet identified. In the initial report of the group, 189 the enzymatic hydroxylation of BaP could not be detected in nonsmokers in homogenates of placentas frozen immediately after birth and studied within 48 h. In contrast, the enzyme activity was present in all 11 placentas from women who smoked during gestation, although enzyme activity in this small group did not correlate with the number of cigarettes smoked. BaP administration to pregnant rats also was shown to induce AHH activity in the placenta. The effect was related to PAH dose. This study constituted the first demonstration that compounds in cigarette smoke could induce a carcinogen-metabolizing enzyme in human tissues. These studies were 6-18

extendedl90 to related enzymatic reactions in human placentas and to other types of pyrenes as probes for AHH-inducing activity in rat placenta (see Table 6-6~. Extremely active inducers included chrysene, 1,2-benzanthracene, pyrene, 3,4-benzofluorene, and a number of related compounds. 90 The wide variability in the induction of AHH activity in human placentas is exemplified by the data in Table 6-7--a range in activity of the enzyme in smokers approaching 1,000-fold (a nearly 2,000-fold range if smokers are compared with nonsmokers). The basis for this extreme range of responses to a chemical exposure (15-20 cigarettes/d for each subject) is not known. However, data presented by Harris et al.70a suggests that pulmonary alveolar macrophages can metabolize BaP to proximate and ultimate mutagens released into extra- cellular space. LUNG - The respiratory tract comprises an extremely disparate and complex set of tissues containing some 40 different cell types.166 As Devereux et al.47 have noted, whereas pulmonary cytochrome P-450 and the metabolism of xenobiotics have been studied with various preparations of lung tissue (microsomes, isolated perfused lung, cells obtained by pulmonary Savage, direct instillation of xenobiotics in various portions of the respiratory tract, etc.), little is known about the localization of the cytochrome P-450 monooxygenase components in the pulmonary system. This section deals exclusively with the metabolic properties of human respiratory tissues with respect to PAH metabolism, but the lack-of information just cited needs to be kept in mind. There are facets of the investigation of Devereux et al.47 in rabbits that probably bear significantly on problems of human pulmonary tissue biotransfo'=ations that depend on cytochrome P-450; these aspects include the observation that the alveolar macrophage that accumulates PAH has little or no measurable cytochrome P-450 or monooxygenase activity58~71~148 and that there is selective cellular distribution of cytochrome P-450 species. The ability of human bronchial epithelial cells to bind and presumably to activate such PAHs as 7,12-DMBA, 3-MC, BaP, and dibenz~ahianthracene was described by Harris and colleagues in 1974.7 Four tissue samples were studied (one control and three lung cancer) in explant cultures, and radiolabeled PAHs were used; radioactivity from all four compounds tested was found in both cytoplasm and nuclei and in all tissue samples studied (see Table 6-8~. The number of tissues examined precluded comparisons between normal and tumorous lung PAH metabolism adduct identification were carried out, ~ activity from the labeled PAHs was found tightly by CsC1 gradient. A more detailed study by this tissues obtained from an additional four patients pulmonary malignancy. and no studies of PAM-DNA althou~h, as noted, radio- bound to DNA isolated groupl95 used , three of whom had Explants of human bronchi also metabolized BaP and released deriv,iives that are mitogenic in the Chinese hamster V-79 cell line. The 7,8-diol of BaP was approximately 5 times more potent as a promutagen than the parent PAH; binding of the diol to DNA was 5-20 6-19

times greater than that found with BaP. When 13 samples of bronchial cells were studied with cloned Chinese hamster V-79-4A cells, a positive correlation between ONA-PAH binding (in the cultured bronchial cells) and induction of Or (ouabain-resistant) mutants was found, but no correlation between this mutation frequency and AHH activity was identified. This may be attributable, as the authors noted, to the difficulty in correlating AHH activity with the consequences of the multistep pathway of metabolic activation for BaP. The individual variation in mutation frequency was 9-fold, and the variation in binding of PAH to UNA 5-fold. This important investigation pointed the way toward study of the metabolic activation of chemical carcinogens into promutagens and mutagens directly in differentiated epithelial cells derived from human tissues; and the human tissue-mediated mutagen assay opened the possibility of testing the hypothesis that people differ in mutagenic and oncogenic susceptibility to environmental chemicals, depending on individual capacity to activate and deactivate chemical procarcinogens. Autrup et al.12 compared the metabolism of BaP by cultured tracheobronchial tissues from humans and four other species (mice, hamsters, rats, and cows). They provided evidence that the metabolism of BaP is qualitatively similar in tracheobronchial tissues from humans and from animal species in which PAHs have been shown experimentally to be carcinogenic. A similar study limited to a comparison of human lung microsomal fractions and rat microsomes was carried out by Prough et al.144 The results indicated that human microsomes form a higher percentage of dihydrodiol products from BaP than do rat microsomes. The wide variation of PAH metabolize profiles formed by the 15 samples of human lung studied may be due in part to differences in clinical diagnosis when the samples were obtained. Bronchial tissues cultured in a chemically defined medium were exposed to radiolabeled BaP or its metabolizes, and their binding to TUNA was measured. Radiolabeled metabolizes were prepared by incubating the parent PAH with rat liver microsomes and then purifying and identifying with silica gel and HPLC. The binding data showed that (-~-trans-7,8-diol bound to bronchial mucosal DNA to a considerably greater degree (S- to 23-fold) than did BaP; binding was also much greater (25- to 80-fold) than with the (-~-trans-9,10-diol. The trans-7,8-diol constituted 3-6% of the total identified metabolizes when human bronchi were exposed to BaP. Diol-epoxides were formed from (-~-trans-7,8-diol in two of the bronchial explants, and strong evidence was provided that the major tumor bronchial mucosal DNA-binding BaP metabolize is in fact derived from (-~-trans-7,8-diol.195 The specific adducts formed between DNA and the metabolic intermediates of BaP were not isolated, but the author concluded that the predominant bound metabolite is a single enantiomer of diol-epoxide I derived as indicated above. In an extension of their earlier work, Harris and colleagues69 examined the metabolism of BaP and 7,12-DMBA in explants of human bronchus and made a metabolic comparison with human pancreatic duct explants. As in the prior study, both normal and malignant human bronchi (37 subjects) metabolized BaP actively and in generally similar 6-20 hi . .

fashion, except for a higher percentage of organic-solvent-extractable metabolites formed by bronchi from noncancer patients. In addition, prior exposure of the bronchial explants to benz~aJanthracene altered the qualitative features of the metabolite profile of BaP, as analyzed by HPLC. Benz~aJanthracene specifically increased the binding of BaP to cellular DNA and the activity of AHH. Among a group of 28 of the patients' tissues studied, 7,12-DMBA was bound to DNA more often (26 of 28) than BaP. In the comparison with pancreatic duct explants, 7,12-DMBA-ONA binding was consistently lower in the latter tissue than in the bronchial explants. Cohen et al.34 showed, with cultured human bronchial epithelium, that BaP was converted promptly to metabolites that cochromatographed with 9,10-dihydro-9,10-dihydroxy-BaP and 7,8-dihydro-7,8-dihydroxy- BaP. Similar results were obtained with human lung cultures, except that a major metabolite, benzota~pyrene-3-yi hydrogen sulfate, was identified. The biologic activity of this sulfate ester of 3-hydroxy- BaP is of interest, because, owing to its physicochemical properties, it could be extremely persistent in man. - Covalent adducts between DNA and BaP in treated cultured explants of peripheral human lung tissue and in the continuous human alveolar tumor cell line were identified by Shinohara and Cerutti.161 From the chromatographic analysis of digests of ONA extracted from these tissues, it was concluded that both the lung specimens and the human alveolar tumor (A549) cells metabolized BaP to diastereomeric 7,8-dihydroxy-9,10-epoxytetrahydro-BaP intermediates that mostly reacted with the exocyclic amino groups of deoxyguanosine to form N'-~10-t 76 , 8a , 9a- and 96-trihydroxy-7,8,9,10-tetrahydro- benzotaipyrene~yl~deoxyguanosine (dGua-BaP I and II). Although comparable amounts of dGua-BaP I and II were formed in A549 cells, dGua-BaP I was the predominant adduct in the DNA of lung specimens from six different donors. The wide range of metabolic capacities for PAHs exhibited by other buman tissues studied also extends to lung tissue, as shown by Cohen et _ .35 They observed a 44-fold variation in the ability of short-term organ cultures of peripheral lung tissues from human cancer patients to metabolize BaP to organic-solvent-soluble derivatives. The total amounts metabolized ranged from 1: to 96.2t in a 24-h culture period. The authors concluded that, although caution must be exercised in measuring metabolic activities of human tissues derived from diseased patients, the use of short-term organ explant cultures mimics the in vivo metabolic disposition of PAH better than the use of lymphocyte AHH activity would. A solution to the practical problem of obtaining lung tissue from large populations to study the validity of this conclusion is not apparent. Kahng et al.78 concluded from a study of 11 immediately autopsied subjects that bronchial tissue exposed to benz~aJanthracene produced induction responses of AHH that correlated with induced AHH activity in monocytes from the same subjects. A reconfirmation of the wide range 6-21 ~; ~... .

of individual differences in AHH activity of surgically obtained specimens of normal lung tissue (86 subjects) came from a detailed study by Sabadie et al. 53 Briefly, AHH activity was lower than nonequal in tumorous lung sections in 73 of the 86 patients; and in 22 tumor tissue samples, no AHH activity was detected at all. Individual variation (excluding the 22 subjects) in lung-tumor AHH activity was 20-fold, which approximated the variation observed in other studies, including those in which PAM-DNA binding and pulmonary tract tissues were studied. BaP metabolite formation was analyzed, and the results generally conformed with the data of other investigators. Interestingly, BaP (but not pyrene) induces AHH and prolyl hydroxylase activity in neonatal rat lungs in organ culture.74 Because prolyl hydroxylase is an indicator of collagen synthesis and increased activity of this enzyme in lung reflects increased collagen formation, the authors, Hussain et al., hypothesized that the earliest events in BaP-induced lung injury may include alterations in collagen metabolism. In a study of-the effect of tobacco-smoke compounds on the plasma membrane of cultured human lung fibroblasts, Thelestam et al.175 examined 464 compounds, of which nearly one-fourth gave rise to severe membrane damage. PAHs proved inactive in this test system; the PAHs tested included anthracene, benz~aJanthracene, chrysene, pyrene, BaP, perylene, fluoranthene, and coronene. The significance of these findings is not entirely clear, but, inasmuch as very large concentrations of the compounds were used (25 mM), the failure of all PAHs tested to cause substantial release of the radiolabeled nucleotide material from the cells suggests that PAH entry into cells of organs in which their carcinogenic potential is expressed does not require as an initial event plasma membrane damage by the active chemical species. Lung damage by ozone59 and nitrates183 showed contradictory effects: in the former case, adaptation may become apparent, and, in the latter, susceptibility to infection may increase. In the case of asbestos-produced damage, as well as damage produced by other particles--such as iron oxide, silica, and carbon black--cellular uptake and availability of BaP increase.97~99 Asbestos, of the several particles tested, was particularly effective in increasing microsomal uptake of the PAH, although clearly adsorption of the PAH on the particles--rather than simple mixture of the two--is required for the increase in cellular uptake to become evident. The relevance of these findings to the phenomenon of particle-PAH cocarcinogenesis is clear.99 BaP elusion from typical soot from pollution sources, as well as from soot in lungs (11 cases), has been carefully studied by Falk _ al.56 Strikingly, this PAH could not be recovered from soot in human lungs without malignancy (Table 6-9), whereas the noncarcinogen pyrene could be identified (in much lower concentrations than expected). Adequate controls appeared to ensure that the disappearance of the carcinogenic PAH was a biologic phenomenon taking place in vivo; the authors concluded that elusion must have occurred in the host through an undefined mechanism. In another study, 178 involving 21 bronchial carcinomas, a searc'n was made for 12 PAHs in the tissues with chromatographic and fluorescence techniques. Only four of 6-22 ~... ..

the 12 PAHs sought were found: BaP, fluoranthene, perylene, and benzotbifluoranthene (Table 6-10~. BaP was found in all tumors; fluoranthene and benzotbifluoranthene were sometimes present, as was perylene. Coronene, dibenz~ah~anthracene, pyrene, benz~aJanthracene, chrysene, benzotghi~perylene, benzo~k~fluoranthene, and benzo~e~pyrene were, if present, below the limits of detection. HUMAN EXPOSURES TO PAHs: A BRIEF SUMMARY The studies reviewed in the preceding sections were related primarily to the metabolic interactions of PAHs and human tissues and focused principally on the oxidative reactions known to convert many of these compounds to potent mutagens and carcinogens. This section reviews a number of reports dealing with possible detrimental health effects of specific workplace exposure to PAHs and representative reports dealing with PAH contamination of the aquatic environment and of foods. The literature on atmospheric exposure to PAHs is dealt with elsewhere, except for exposures that are discrete and intense, as in some working environments. In the light of this review, one cannot avoid the conclusion that the greatest present source of human PAH exposure is through the gastrointestinal tract; nor can one disagree with the statement in the 1970 Royal College of Physicians report1 that, to the extent that PARs ere involved in the genesis of pulmonary malignancies, "by far the most important matter affecting all . . . aspects of mortality from lung cancer is spoking." The equally emphatic conclusion of Pike and Henderson1 1 that "the epidemiologic evidence implicating cigarette smoking as the major cause of lung cancer is overwhelming" puts the clinical studies reviewed here related to the potential pulmonary hazards of atmospheric PAHs in proper perspective. WORKPLACE EXPOSURE Schenker in 1980155 reviewed the question of whether diesel exhaust is an occupational carcinogen and summarized a number of the principal studies (Table 6-11) on the question of cancer incidence in populations of workers exposed to diesel exhaust. Data on environ- mental and occupational BaP and total suspended particles in various urban and rural sites and specific occupations were also provided (Table 6-12~. These epidemiologic data emphasize the conclusion that "the carcinogenicity of workplace exposure to diesel engine exhaust is suggested . . . but the existing data are sparse and contradictory." Table 6-11 shows only concentrations of BaP, and the values are in units of micrograms per 1,000 cubic melters. Because the air breathed by a normal adult approximates 15-20 m /d, the highest PAH concentra- tion shown indicates a potential exposure dose of about 700 Aged in a work setting (coal and pitch-coking plant) known to have one of the most intense PAH exposures. This figure exceeds by orders of magnitude the exposure produced by the heaviest smoking, and such an occupational locale would thus be expected to elicit detrimental and clearly detectable health effects in man. The same consideration applies to 6-23

the data on workers in gasworks retort houses and roof tarrers. But beyond these specific occupational sites, the respiratory intake of BaP--even if, for occupational purposes, a person had to remain for 24 hid in Blackwall Tunnel, London (Table 6-11~--would approximate that from about a pack of old-style cigarettes per day. The improbability of such occupational exposures emphasizes the difficulty of measuring the health hazards of atmospheric PAR sources in the general sense (i.e., in the 28 rural and 24 urban sites depicted in Table 6-11~. A number of occupational-epidemiologic studies have emphasized the difficulties of reaching firm conclusions with respect to the direct (or measurable) health risks of PAHs in work environments, whether the suspected hydrocarbon comes from diesel or other automotive exhausts or from chemicals, such as petroleum sources, that are intrinsic in the occupation itself. Battigelli et al.18 studied 210 locomotive repairmen (average age, 50 yr; average work period, 10 yr) considered to be regularly exposed to diesel exhaust and 154 "control" railroad workers. The studies were carried out in two railroad shops in Pittsburgh, Pa. The clinical data were scanty, and it was not possible to differentiate the exposed from the nonexposed worker population on the basis of pulmonary-function tests. However, smoking clearly impaired the pulmonary functional performance of workers. A somewhat comparable environmental study carried out by E1 Batawi and Noweir55 in two diesel-bus garages in Egypt raised the possibility of clinically detrimental, synergistic effects of smoke and acrolein gas, which is known to be present in exhaust of diesel engines. Ventilatory-function changes over a workshift in coal miners exposed to diesel emission were studied by Reger et al.;147 the only positive finding in this study of 800 men was that smokers suffered consistently greater pulmonary- function decrements over a workshift than nonsmokers. In a retro- spective study of mortality statistics,83 Kaplan could identify no higher than normal rates of death from bronchopulmonary carcinoma in workers exposed to fumes from diesel engines among the medical records of 6,500 deceased railroad workers, including 818 deaths from malignant diseases. Lloyd et al.109 reported that the mortality from respiratory cancer for men employed in a coke plant was twice the rate generally observed among steelworkers; the whole difference was accounted for by a threefold excess for nonwhite workers. A more detailed analysisl08 showed the following: The excess of respiratory cancer previously reported for coke-plant workers was limited to men employed at the coke ovens, the relative mortality for this disease being 2.5 times that predicted. The greatest part of the excess was accounted for by an almost fivefold risk of lung cancer in men working on the tops of the coke ovens. A 10-fold risk of lung cancer was observed for men employed 5 yr or more at ful 1-time topside jobs; 15 lung-cancer deaths were observed among the 132 men in the topside group ? compared with 1.5 expected. The apparent differential in respiratory-cancer rates for white and nonwhite coke-plant workers reported in an earlier paper was accounted for by differing distributions by work area and the unusually high lung-cancer risk for topside workers; lung-cancer mortalities for 6-24 ~. . . ..

white and nonwhite coke-plant workers employed at work stations other than topside were comparable. A deficit of deaths from heart disease, previously reported for similar occupational groups, was also seen for coke-oven workers. Coke-plant workers employed only in nonoven areas may be at excess risk of digestive cancer. A review of the literature on cancer mortality of men employed in the coal-tar industries showed that all these occupations evidence excess cancer at one or more sites. The lung-cancer excess in coke- oven workers also was observed in other groups engaged in coal carbon- ization, and it appeared that the lung-cancer response was positively correlated with the temperature of carbonization. Among coke-oven workers studied by Mazumdar et al.,117 excessive deaths from respiratory malignancy were reported. As in the study of Lloyd et al. ,10 there was a tendency for the death rates of nonwhite workers to be higher than those of white workers. Measured concentra- tions of coal-tar pitch volati les in the environment of men who worked at the top of coke ovens were 2-3 t imes 1,igl~er than in that of men employed at the side of the ovens. High BaP emission, among others, has been measured in the gaseous discharge--including the coal-tar pitch volatiles--of coke ovens in the steel industry, a rough est imate being that 1.8 g of this chemical is emittelO;er ton of coke produced.117 As in the Lloyd et al. study, the overall cancer-death risk for coke-oven workers was distinctly higher than that for normal persons in the age group over 55 yr, and the age-adjusted death rates for lung cancer showed a strong relationship between extent of exposure to coal-tar pitch volatiles and tung-cancer mortality. The lowest-exposure groupll7 had death rates similar to those of nonoven workers, but all higher-exposure groups had age-adjusted rates that ranged from 3 to 10 times those of the comparison group with increasing exposure. The data in this study also confirmed the long latency in cancer formation, even under the conditions of high exposure to carcinogens characterizing coke-oven workers; the time between first exposure to coal-tar pitch volatiles and death from lung cancer varied from 10 to 40 yr, with an average of 25 yr. Toxicologic experience with workers in the developing shale-oil industry is incomplete, although historical evidence indicates that potential health hazards related to malignancy may exist in the processes involved in oil extraction.187 Some data on the content of BaP and pyrene analogues from shale materials, as reported by Weaver and Gibson, 187 are useful to record here (Tables 6-13 and 6-14~. Because the industry is still in its developmental stage in this country, the overall health impact that may be attributed to exposure to these PAHs--as well as to other contaminants such as arsenic, beryllium, cadmium, lead, mercury, and nickell8~--~s difficult to estimate. 6-25

EXPOSURE TO PAHs VIA THE GASTROINTESTINAL TRACT The exposure of humans to PAHs may be cons idered to be almost exclusively via the respiratory and gastrointestinal tracts. Some occupational groups (e.g., the chimney sweeps studied by Pott) may have an intense local cutaneous exposure to PAHs, but the significance of percutaneous absorption of these compounds for the general population is not known. Such substances as the polychlorinated biphenyls22 and constituents of coal tar can pass through the skin and induce liver oxidative enzymes in animals, so it is possible for some Undoubtedly small) degree of PAH accumulation to occur in humans systemically via . . s con exposure. Several major reviews of the importance of water and food as vehicles of human exposure to PAHs have been published in the last 5 yr. These include a special issue of the Journal of Environmental Pathology and Toxicologyl54 devoted to the health aspects of PAHs and several monographs focusing on PAHs in drinking-water sources and on PAHs in the marine environment.l9,l29' PAHs in Water It can be stated at the outset that human exposure to PAHs through the ingestion of water is quantitatively insignificant, compared with exposure through food--the contribution of drinking water is estimated to be only about 0.1% of the total PAH derive] via the gastrointestinal tract in humans.3 This estimate, carrying with it an implicit assumption of relative biologic safety (at least compared with foods as a source of PAHs), is probably valid except perhaps for some surface-water sources, which, because of location (e.g., downstream from shale-o'1 effluent or c~ke-byproduct discharge sites--see Table 5-12 of Santodonato et al.15 ), may be heavily contaminated by such PAHs as BaP. Groundwater concentrations of this prototype PAH determined in multiple German and Amerigan sources are extremely low (see Table 5-11 of Santodonato et al.154), ranging from a fraction of a nanogram per liter to several nanograms per liter. The average "total" PAH content is, of course, greater, but still in the same range. In contrast, low- to medium-concentration contaminated surface waters may contain PAHs 5-20 times higher, and this pollution may be increased by several orders of magnitude in sewage water or in surface waters adjacent to industrial sites. Treatment of surface water to obtain drinking water can nevertheless remove the bulk (95% or more) of the PAHs, particularly with activated-carbon filtration. This reflects the fact that muck of the PAH in water subject to pollution is quickly adsorbed on suspended solids or is found in sedimented particulate matter. The majority of PAH entering surface water is concentrated locally; although PAH can probably be considered ubiquitous in water, the amounts involved are substantially lower than those found in air or on land. Neffi29 has pointed out that, if all PAHs found in the aqueous environment were distributed evenly throughout the oceans and fresh-water bodies, they would be undetectable and inconsequential. 6-26 ^. .. .

As noted, the PAH content of drinking water is, with an occasional exception, low, as expressed as BaP and total PAH (Table 6-159.154 Among the general class of PAHs, the compounds that have been detected by high-resolution gas chromatography after extraction from tapwaterl32 are listed in Table 6-16 with their concentrations. Such contamination at a typical, most proximate (tapwater) drinking-water source represents only trace contamination, compared with the PAH content of original fresh-water sources, marine and estuarine waters, fresh-water and marine sediments, and some alcoholic beverages.179 The occurrence of PAHs in saltwater sources has for several reasons more potential biologic importance than the occurrence of these compounds in drinking water. The oceans provide a very large surface area for deposition of airborne PAHs via rain and dry fallout. Runoff of PAHs from the land surface also contributes substantially to marine-water content, as do direct effluents from sewage and industry. Carcinogenic PAHs occur in crude and, particularly, refined oils, 3 and oil spills may contribute in a major way to marine pollution with these compounds, especially on a local scale. -The oceans constitute an ecosystem in which varied animal and plant life can participate in the metabolic processes involved in the uptake, storage, concentration, biotransformation, and discharge of PAHs. Thus, the consumption of fish and shellfish of predominantly saltwater, compared with fresh-water, origin (88% vs. 12% of the seafood in the diet) gives special importance to the PAH contamination of the aquatic environment that these food species inhabit. PAHs are universally, although unevenly, distributed throughout the marine (saltwater) environment. They are derived principally from atmospheric fallout, terrestrial runoff, and spills of petroleum pro- ducts. The contribution, if any, of marine organisms to PAH pollution by de novo biosynthesis is unknown. Total PAH entry into the marine environment from petroleum spills is estimated at 17 x 104 tons/yr, of which BaP would constitute 20-30 tons/yr.129 Conservative figures for the total world contribution of industrial and domestic wastewaters to marine pollution with PAH have been estimated to be BaP at about 29 tons/yr and total PAH at 4.4 x 103 tons/yr. For terrestrial runoff, the figures are about 118 tons/yr and about 2.9 x 103 tons/yr, respectively, and for atmospheric fallout, 500 tons/yr and 50,000 tons/yr. Because the composition of total PAH in these sources varies considerably, it has been suggestedl29 that the figures estimated for BaP input provide a better index of the potential carcinogen input from these sources than do the figures for total PAH. The majority of PAH in the aquatic environment remains near the point source of contamination and thus is concentrated in coastal waters; here, the bulk of the PAH is in bottom sediments and to a lesser extent in suspended solids or solution. The water solubility of carcinogenic PAHs is very low, but solubilization may be increased by the concurrent presence of detergents and other organic substances. Pnotodegradation of PAHs in the marine environment can occur variably, 6-27 ~. A .

depending on the depth and turbidity of water and other factors; hut persistence of PAHs is much greater in water than in air, because the particulate matter on which these compounds are mostly adsorbed provides a storage pool from which they may be slowly returned to water by leaching or through biologic processes involving marine organisms. the The characteristics of marine pollution by PAHs are such as to suggest the occurrence of multiple varieties of discrete ecosystems with relatively high concentrations of these compounds in sediments and local plant and animal species--all existing in a vastly larger aquatic environment characterized by a smaller degree of PAH contamination. In the local marine areas of high PAH pollution--principally river basins and estuarine and coastal waters--the degree of PAH contamination and the PAH composition in water, sediments, and nonmigratory marine life are determined by the nature of the point sources of contamination. In the organisms found in these areas, the PAH composition depends on metabolic processes related to the selective bioconcentration, biotransformation, and accumulation of the PAHs or metabolites or their discharge into the aquatic environment. The fate of PAHs in marine ecosystems has been studied by Lee et al.,l°l who used as a model Prudhoe crude oil enriched with a number of PAHs dispersed into a controlled ecosystem (polyethylene enclosure 2 m wide and 15 m deep) suspended in Sadnich Inlet, Canada. The oil was estimated to contribute PAHs at Concentrations ranging from BaP at 100 ~ to nap~thalene at 300 x 10 fig per 100 g. Multiple water and sediment sampling, microbial-degradation studies, analysis of bio- accumulation by oysters, and analysis of adsorption to sediments with [14C]PAH were carried out. The results demonstrated a rapid, marked decrease in PAHs from water (half-life, 3-4 d) and a variable recovery, depending on the PAH, in the sediment. For the low-molecular-weight PAH napUthalene, this recovery was only 7X after 1 wk; for BaP, it was 39%. Oysters rapidly took up all PAHs, but released naphthalene to such an extent that it was not detectable in the organisms after 23 d. In contrast, benz~aJanthracene and BaP were released much more slowly, with estimated half-lives (assuming exponential discharge) of 9 and 18 d, respectively. Thus, the higher-weight PAHs persisted much longer in the organisms than the lower-weight PAHs. Other degradation studies involving mussels collected from oil-contaminated waters also have shown the persistence of the higher-molecular-weight PAHs.51~53 Evaporative loss of lower-weight PAHs, such as naphthalene, in the upper waters was expected, whereas this would be limited for higher- weight PAHs. Microbial degradation of napUthalene and anthracene was measurably increased in oil-contaminated water, compared with control water (4 h vs. 48 h, respectively, for appreciable degradation)--a finding consistent with those of other studies showing higher numbers of oil-degrading microorganisms in polluted than in control or unpolluted waters. Photochemical degradation of PAHs was inferred; for BaP, this was considered to account for an amount that could approximate about 50% of the compound, inasmuch as no microbial degradation of the compound was demonstrated and 407 was recovered in 6-28

the bottom sediment. The study permitted several conclusions that probably have general relevance. The half-lives of PAHs in marine waters are short (a few days); for lower-weight PAHs, microbial degradation and evaporative loss may be primary removal processes; for higher-weight PAHs, such as BaP, sedimentation and photodegradation are the most important removal means; and, by inference, for higher-weight PAHs after sedimentation, biologic degradation and interaction between plant and animal life in the sediment are important factors in removal. These processes (biologic degradation and interactions) have been extensively studied with a wide variety of aquatic species. It is clear that, as with terrestrial fauna, the capacity of marine animal species to effect the metabolic transformation of PAHs can be considered to be universally distributed. Reviews of the results and other aspects of such studies have been published elsewhere,334337338,l29,l8l and only representative reports are summarized here. PAHs in the marine environment can be metabolized by aquatic bacteria and fungi;129 for some species of bacteria, a monocyclic aromatic hydrocarbon, such as benzene, can serve as a sole carbon source. PAHs, such as BaP and benz~aJanthracene, can also be oxidatively metabolized to hydroxylated derivatives comparable with those produced in the livers of vertebrates. PAHs can be degraded to CO2 to a considerable degree (13-68%129) by aquatic microorganisms. PAH metabolism by fungi also occurs; these organisms contain cytochrome P-450 and can carry out the initial oxidative metabolism of PAHs in a manner resembling that catalyzed in vertebrate liver. Marine fungi isolated from oil-polluted water or oil slicks have a substantial ability to assimilate petroleum hydrocarbons, and this hydrocarbon-degrading capacity can permit use of a PAH as a growth substrate.] Fish and crustaceans (and some worms) can oxidize PAHs--as measured by AHH activity--and cytochrome P-450 has been identified in a number of these species. Most oxidative metabolism in these aquatic animals is in the liver, as it is in mammals. Induction of cytochrome P-450 (not always correlated with an associated P-450-dependent increase in chemical oxidation) in fish has been produced by benz~aJanthracene, chrysene, BaP, and other organic substances33~6l~l29,l40,l69 to which fish may be exposed in their natural environments or under experi- mental conditions. The products of the oxidative metabolism of PAHs in fish resemble those produced in mammalian liver and include dials, epoxides, phenols, quinones, and all principal types of conjugates formed from PAH metabolites in mammalian liver. Seasonal changes in P-450-dependent oxidation have been reported in fish,49 and alterations in this enzymatic activity have been related to ambient temperature, food status, and exposure to inducing chemicals in their natural habitat.48349 Apart from carrying out biotrans- formation, the capacity of marine species to accumulate and discharge PAHs from the surrounding waters is important in relation to the pattern of distribution of these compounds in the marine environment and to the use of marine species as food, in view of their contribution to the exposure of humans to PAHs via the gastrointestinal tract. 6-29 Hi;

Marine animals readily accumulate PAHs from the surrounding waters and can discharge both the untransformed PAHs and their metabolic products into the aqueous environment. The rates of release of accumulated PAHs may vary substantially from species to species (and compound to compound), and half-lives can range from hours to many days. The substantial concentration gradients of PAHs that may occur between an organism and its aqueous environment can have importance for man in r44ali2nl93 marine species that are eaten by man or by edible species. ~ ~ Whether these concentration gradients involve an active uptake mechanism is not known; but they do not depend solely on solubility, inasmuch as polar metabolites of a PAR can be retained longer than the more lipophilic parent compound.l3 This may be due to the electrophilic nature of these metabolites and their consequent binding to tissue macromolecules.129 Oysters have been shown to concentrate hydrocarbons from diesel-oil- contaminated waters to concentrations over 300 fig of total hydrocarbons per gram of wet weight over a 7-wk period.170~17I These hydrocarbons were rich in aromatics, compared with the contaminating oil. In clean seawater, the hydrocarbon concentrations decreased dramatically (by 90% in 4 wk). Other marine species show the same biologic characteristics, although uptake and release of accumulated hydrocarbons vary. The con- centration factor (i.e., tissue vs. water concentration) may reach 1,000-fold23 in marine animals that cannot escape a contaminated environment. The potential importance for humans of this capacity for bioaccumulation in edible marine species is evident. PAHs can, as expected, accumulate rapidly in fish from contaminated sediments, as McCain _ al.118 have shown, although this process is less efficient than uptake from water. The biologic impact of contaminating PAHs on marine species has been thoroughly reviewed recently37~38~46~93~129 and is t summarized here. Toxic effects of these and related pollutants have been described across the spectrum of marine life, from bacteria and fungi to plants and animals; and they range from the "tainting" of commercial species37~38 to the development of cancer and cancer-like growths in aquatic animals.46~93 PAHs in Food The exposure of humans to PAHs from dietary constituents greatly exceeds that from any other sources except specific hazardous occupa- tional settings. PAHs are ubiquitous contaminants of foods and-- depending on the extent of atmospheric and soil pollution in crop areas and on methods of processing, preservation, and preparation--can become highly concentrated in selected foodstuffs. At least 100 types of PAHs have been identified in foods.201 Some of these have been shown to have well-defined carcinogenic properties in experimental animals. Epidemiologic studies have suggested an association between the consump- tion of high-PAH foods and gastrointestinal malignancies in selected 6-30

populations 106,165,177 but it is difficult to extend this associa tion to the general population or to define the biologic risk of PAHs in foods in more direct terms. Nevertheless, the quantitative dimen- sions of PAH exposure via the diet and the established carcinogenic potential of some of the compounds frequently identified in foods suggest that the health risks from this source of exposure, although still incompletely defined, may be important for various groups. Edible marine species may contain variable amounts of PAHs derived principally from polluted terrestrial runoff waters, from marine sedi- ments, and from petroleum-contaminated aquatic environments. As noted above, such environments are largely in-shore (e.g., estuaries and river basins), with pollution diminishing rapidly in the open seas. Bioaccumulation of PAHs in the marine food chain may be substantial in some fauna, and, of course, national predilections for such modes of seafood preparation as smokingl4~64~67~114,l76 can increase to high values-the content of PAHs in such foods. The potential for biomagni- fication of PAHs in aquatic food chains is clear, but the extent to which this process results in contamination of seafood ingested by humans is not known (the subject has been reviewed by Neffl29~. For some crustaceans and fish, PAH uptake through the food chain can be more efficient than uptake from the surrounding waters,44~102~193 and storage of such compounds in these species can be substantial. PAHs thus stored may or may not undergo extensive biotrans foams Lion. The processes of storage, uptake, metabolism, accumulation, and excretion have generally large interspecies variation; but crustaceans appear relatively efficient in their uptake of PAHs from food and other sources.l29 Table 6-17 shows an analysis of PAHs in oysters collected in a moderately polluted harbor area by C ahomann and Kuratsune.30 The comparative BaP and benzanthracene contents of a variety of foodstuffs are shown in Table 6-18. (Also, see Table 6-21 for similar information on benzote~pyrene, chrysene, and dibenz~ah~anthracene.) The extent of and striking variation in PAH contamination of marine species are evident in the data (Table 6-19) of Mix and Schaffer, 126 who examined BaP concentrations in mussels (Mytilus edulis) in Yaquina Bay, Ore., at multiple sites over a 2-yr period. The variations have a time component, geographic determinants, seasonal and environmental elements, and unknown biologic influences that make generalizations from such data extremely difficult and perhaps impossible. The BaP concentrations in mussels reported by this study exemplify, however, the extent to which marine species have the potential for representing a considerable exposure source of PAHs in the human diet. A variety of foodstuffs of terrestrial origin have been analyzed for PAH contamination, and many PAHs have been identified. They include the polycyclic compounds listed in Table 6-20, some of which have known carcinogenicity.126 The known carcinogens 7,12-DMBA, cholanthrene, and dibenzotai~pyrene have also been identified in curing smoke. The relative concentrations of five carcinogenic PAHs in a sam- pling of foodstuffs are shown in Table 6-21.20 It is clear from these data that amounts of some of these foodstuffs that are well 6-31

within the amounts ingestible within a 1-d period constitute a PAH exposure via the gastrointestinal tract that can greatly exceed the pulmonary exposure of a very heavy smoker to PAHs. Large amounts of PAHs can be found in soils and can enter food crops from this source. Table 6-2225 shows results of a sampling of soils in the Northeast for BaP. The concentration of PAHs in soil can vary over an enormous range; for the prototype compound BaP, Bauml9 has summarized World Health Organization data showing a range (in micrograms per kilogram of soil) extending from around 100 (nonindustrial sites) through 1,000 (towns and vicinity) and 2,000 (soil near traffic) to 200,000 (soil near an oil refinery) or even over 600,000 (soil directly contaminated by coal-tar pitch). The nigher figures reflect particle deposition, local atmospheric fallout, and direct waste discharge; the origin of the PAHs in forest samples (whose soil concentrations range up to 1,300 ~g/kgl9) is not certain, but must include a large contribution from natural combustion. PAHs in food crops are probably derived in part from polluted soils, although the relative contribution of this source, compared with irrigation water or atmospheric pollution, is not established. PAHs in soils can be translocated to plants, probably through root adsorption, but the extent to which this occurs does not seem to correlate with the P.\H content of soil.89~159,l84 Uptake of PAHs may also vary with plant species. The aboveground parts of edible plants can, of course, also concentrate PAHs through surface absorption from deposited dusts containing these compounds. Through this process, the aboveground parts of food crops can accumulate a gradient of PAH contamination exceeding that in root parts by a fac tor as high as 10, 89 and the bulk of this contamination in such edible crops as leafy vegetables (e.g., lettuce, spinach, and kale) and tomatoes cannot readily be removed by washing. 184 PAH contamination of irrigation wastes also contributes to an unknown extent to the contamination of edible plants. In the processing of foods, packing materials and additives are other sources of potential PAH contamination. By far the largest sources of PAH contamination of foods are curing and preserving processes and cooking, especially of meats. Apart from shellfish, the "intrinsic" content of PAHs in most foods is low; for example, uncooked pork and beef may contain only 0.1 ~g/kg. This con- centration can increase substantially as a result of any cooking pro- cess (see Table 6-21) and especially as a result of smoking, curing, or broiling under a direct flame in which food drippings can be pyrolyzed. PAH contamination of foods associated with smoke-curing results in part from the resinous condensates of liquid smoke flavors and from food combustion products.64,lo6,l~o~l77~9l The type of smoke generation and other characteristics of the smoking process can influence the amounts and types of PAHs produced--e."., the temperature of combustion, the air supply, the length of smoke ducts, and the density and temperature of the smoke-cure. 177 Domestic smoking clearly produces more PAH than the commercial process, 14 probably 6-32

because the procedure is less controlled and, as a result, entails heavier and more prolonged smoke exposure.176 A general survey by the Food and Drug Administration and the U.S. Department of Agriculture of PAH content of smoked foods prepared commercially was reported by Malonoski et al.112 The broiling of meats over an open flame in which fat drippings can be pyrolyzed probably contributes more to diet-derived PAH exposure than any other method of food processing or preparation. Potent mutagens can be produced from amino acids and proteins in foods by high-temperature cooking.36~1l6,l27,l67,l73,l96 This mode of cooking also increases the carcinogenic PAHs in meats to very high concentrations.106 The concentrations of 15 PAHs found in the outer surfaces of charcoal-broiled steaks by Lijinsky and Shubikl06 are recorded in Table 6-23. These concentrations are not unusually high for broiled or smoked meat (as the data in Table 6-21 indicate), nor for dietary constituents that are known to have a high PAH content, such as yeast oils some leafy vegetables and fruits, roasted coffee, and teas.24364~653261 PAHs formed by pyrolysis can be derived (at least with pure substrates) from carbohydrates, fatty acids, and amino acids, and the extent of their production depends on temperature.206 The data of Masuda et al.115 (Table 6-24) show the amounts of 19 PAHs formed from combustion of six potential substrates at SOO or 700°C. Combustion took place in a nitrogen atmosphere; at 300°C, no PAHs were formed from any of the starting materials, but at the highest temperature studied, large amounts were produced from each. Clearly, substantial quantities of PAHs can be formed from these substrates under the pyrolytic conditions used, and, although ordinary pyrolysis takes place in air, the substrates tested are common constituents of foods and common broiling temperatures are within the range of those used in this study. The conditions of broiling heavily influence the amounts of PAHs produced. Fatty meat produces more PAH after broiling than lean meat, and it has been suggestedl06 that pyrolysis of fats dripping onto red-hot coals is the most likely source of PAHs. PAH production in broiled meat clearly depends, in addition, on the closeness of the meat to the heat source, on whether meat drippings reach the heat source (i.e., heating from the top, rather than the bottom), and on whether cooking is quick at high temperatures or slow at low temperatures.104-107 Toxins other than PAHs are also produced by high-temperature cooking; these include the mutagenic-carcinogenic amino acid pyrolysis products described by Japanese and American workers and the N-nitroso compounds formed in cured-meat products, especially bacon and ham.64 It should be noted that these non-PAH substances can be produced at temperatures distinctly lower than those used in conventional broiling and that a large fraction of them may be volatile; thus, redeposition of these airborne substances and their inhalation during cooking are additional toxin exposures that can be related to the diet.146 6-33 A;

An approximate "balance sheet" of the estimated PAR exposure of humans from air, water, and food is shown in Table 6-25.15 Despite a degree of inexactness in these figures--especially for foods--they provide a reasonable perspective of the sources of PAHs that might have an impact on man. It should be evident from these estimates that food constitutes the predominant source of PAHs for humans; even if the contribution from smoking were included, the diet would still be the dominant source. The health impact of the PAHs in the human diet is not known, although, as noted above, an association between the intake of these substances in smoked foods and the occurrence of gastrointestinal malignancies in select populations has been inferred. The remarkably large amounts of PAHs that are ingested, compared with those to which the pulmonary system is exposed (even in heavy smokers), makes it clear that there must be tissue-specific factors related to the disposition of or metabolic responses to PAHs that protect the gut from the deleterious impact that might be anticipated from such exposure. The possibility of detrimental effects of diet-derived PAHs on the gastro- intestinal system will not be so amenable to quantitation as has been the case with respect to smoking and the development of lung pathology. An approach to defining the human metabolic impact of diet con- stituents in general and of charcoal-broiled meats in particular has been taken in the clinical-nutrition studies recently summarized by Anderson et al.5 Several dietary factors were shown to influence potently the oxidative metabolism of various drugs used as model sub- strates for cytochrome P-450- and cytochrome P-448-mediated chemical transformations. It has been shown that isocaloric substitution of dietary protein for carbohydrate substantially shortens the plasma half-times of such drugs as antipyrine and theophylline; i.e., a pro- tein-enriched diet increases the oxidative metabolism of these com- pounds. Opposite changes were observed during periods of high- carbohydrate feeding. Substitution of protein for fat in the diet (a nonisocaloric change) also stimulates the oxidative metabolism of these drug substrates; however, neither high-unsaturated-fat nor high- saturated-fat diets produce alterations in drug oxidation distinct from those produced by high-carbobydrate diets alone. Thus, with respect to influences on microsomal mixed-function oxidases, carbohydrate and fat in the diet appear to be interchangeable. Feeding rats charcoal-broiled beef is known to increase intestinal metabolism of phenacetin.137 Increased oxidative metabolism of this drug, as well as of antipyrine and theophylline, was also observed in the test subjects after short-term feeding (2 portions/d for 4 d) of normal portions of charcoal-broiled beef at meaLtimes.39~84~136 The effect of broiling (in control diets, the beef was protected from the cooking fire with aluminum foil) was striking; during the test-diet period, there was a pronounced decrease in the mean plasma concentra- tion of phenacetin and a comparable decrease in the area under the curve for plasma phenacetin concentration plotted against time. The 6-34 lo. .. . ..

ratios of the mean concentrations of metabolite and unchanged phenacetin at each point studied increased markedly during the charcoal-broiled-beef test period, compared with control periods. The findings suggested that charcoal-broiled beef greatly stimulated the metabolism of this model drug substrate in the gastrointestinal tract or during its first pass through the liver. Smaller, but still substantial, increases in antipyrine and theophylline metabolism during the ingestion of the charcoal-broiled-beef test diet were also observed. . These systematic and pronounced effects of specific dietary manipulations on the metabolism of model drug substrates by the cytochrome P-450-dependent mixed-function oxidase system provide a valuable means for defining the metabolic responses of both normal and subjects to the ingestion of various foodstuffs or foods prepared ways. The physiologic import of s uch c l inical studies can suitable chemical _ . The extent specif ic chemical biotransformations can also be explored by these metabolic techniques. Finally, it may be possible through such clinical studies--in which each subject serves as his own control--to identify patterns of biologic responses to specific foods or food components that might otherwise be obscured by the genetic and environmental diversity of large population groups. ill in various be greatly extended by the judicious selection of substrates for the metabolic systems under to which individuality in man characterizes 6-35 1nvestl~atLon

TABLE 6- 1 PAHs in Human Livera Concentration (wet basis) 1 2 3 4 5 6 (F. 54) (F. 17) (F,65) (M, 65) (M, 51) (M,41) PAN Anthracene 200 240 170 180 140 110 Pyrene 450 460 340 470 310 270 Benz~aJanthracene ND ND N`D ND ND ND Benz oteipyrene ND ND ND ND ND ND Benzotb~fluoranthene 88 81 87 68 53 33 Benzo~k~fluoranthene 15 23 10 17 8 6 Benzota~pyrene 13 21 19 22 10 11 Benzotghi~perylene 59 48 36 45 21 17 Dibenz~ah~anthracene ND ND ND NI) ND ND aReprinted with permission from Obana et al.130 Numbers in parentheses are sex and age of subject. ND = not detectable - 6-36 .

1 ~ ~ ¢ ·c In D:~ ¢3 a_ o em C0' C) o Cal 1- O O O I_ Cal O O at O - ' ~ e. O ~O to e~ ~' O O e~e ~ - ' ~ O O' ~O -;t e~ O O ~0 o O. O' ~;te C~ O 1- a~ ~e C) ~3 ~ ' ¢ O O C ~C~C ~D ~e _|C- ~t - ~U) ZU~ o _ ~0 _4 ~a) _ ~' 00 ~. Zt=. c.' Ct O U ~_ ~C~C~ C ~X =~U3. Z ~' : Z_ C~ ' O' ='' ~ O O _l r_ ~e ~e 00 U ~e _ _ ~1^ O O. \0 ~; o Z _ O r~ Z C~ a :: C) S" ~ 5- V ~. . _ ~ ~. . _ . O ~N U ~_ C ~C ~\0 O O t_ S" o o 6-37 . o t_ Z :^ _~ ·r1 ~o - o a) a) ~C 0 a, ~_ o o t. N I_ X C ~- CO Z ~n JJ a~ 0` ~ ~0 .,4. - z . o . ~1 '01 ~1 a,1 o o S~ a, C~ 54 C~ - ~ - N a' ~rl O · - U, . - c S~ S O . - C) a' It ~ a .,' s" ~ ~ C) a) ~

~ ~ ax~ cr ~ ~of ~ · · ·· · · · · ~ l - ~c) ~ ~ ~By ~Ad ~ l · · ~ In ID ~ - ~ - t u) E at: D U. 1J ._' O ~ D up E a) 0 1 ~ co o a' ~ ., Ct . . o A: N a) o I of ~ ~ Uso · ~· ~· ~ ~ ~o Cal o ~ ~ ~ ~ ~o ~o Q) · ·· · · · ·· · ·· ·· ·e Rae cat ~ ~ ~ ~In ID ~0~ ~ ~00 U] O ~ ~ ~ ~ ~ O ~ ~ ~ ~ O .~4 · · · · · · · · · · · · · · · ~ r~ O Cal ~ ~O Cal ~C-) ~A) Can [~ I_ Y C-l C~J C-l C~ ~) ~t~ C~ - ~ ~t ~ _4 U~ cr ~ 0 ~ ~Lr) cr ~ ~ ~r~ ~ 0 0 u~ ·-~ · ~·- · ~·- · ~·~ C ~U~ ~ ~ ~00 ~ ~L~ ~ ~0 ~ O · · · · - ~ ~t_ ~ 00 O CO ~ · · ~ C) U: D a . O ~ .,' O ~ . - ~D =0 ,' ~ ~ c, ~1 cr\ ~ O · · ~ · - r_ 0 c ~ O · · · · e ~ ~ ~d" Ct 4~ ~ ;= ~O O OO OO OC~ ~ ~ O ~ 0 r: · · ~· · · · · · · · ~· O ~ C) O O O O O ~ O ~ 0 · -1 C~ ~ ~1~ ~ ~ ~00 C ~-~ ~C ~C~ ~1 -1 U~\ _4 _1 ~ ~ O m) ( ~l~ ~_I O O ~ ~ E E~ D ~ Lr, oO S~ o o U' ~- Ct o CD o C) . - e U~ C~ · ~ ~ 0 L) C~ ~ a' ¢ P4 =1 ~ C: a) C~ a ~0 =1 1 0 I ~z ~ ~z ~ ~ ^ u' ~ 11 - ~ a) b4 v `_ ~ ~'c cn 0 ~ u O O ~ 1 2 z ~ ~ .,1 ~ - 0 11 11 u) c: e~ e~ Ct 5: =: 6-38 o I O Z ~Z o z a: ^ o 11 E - ~o o E o CD a, 0 0 0 ,, C~ CO CO - e cn S~ U) ~CO .- X a) ~ -/ CO ' =: o :^ ~_ ~ O r~ I . - ~ O u v _~ O C) o~ ct cn 0 ^~ ~ ~ 0 O =: . - ~L O a' CD O O ~ _' . - a) ~ D 0/) O f_ O ~n t_ ~ =: O O · - ~ ~ l ~ ~ ~o o ~ a ,- a.) ~ t_ ~ o .,- ~ o ~ ~ o ) ~o ~ ~ o" 3 . U) ~ . o ~ _ U' _ ~ ^ 1J O V -1 C t~ 1 O .- 1 X o ~ ~ ~ o o =: ~ ~ ~: o ~ ~ ~ I 4- o "C ~ ~ C~ U) a) 3 1 ~ U) ~ o U] ~ ^ ,= - ~ C~ a~ ~ ~o s~ o o L, . - v e 0= O O ~ Ct I ) 5: O ~ x O U) ·^ O ~ O S~ ~ ~ 1 C) v

cl) o ~ ~ 'e on o . - ED a' ~ ~ :~- cd ~ ~ o cC ~ ~ o ~ :^ ED O ~ 1 o ~ D S" V ~ ~ ~ o ¢ a, ~ ¢ O O ~z e ~ - - 1 V c ~1 ~ ~ ' - s ~aJ ~:) D a) <1) "C 0 0 c: s~ 0 a) ~ ~ ~ ~C4 D ;~ O ~ O4 _~ . ~ N O C ~ oe cn ~ O0 1 ~ ~n ~ ~ :^ E ~ ~D ~ O O c a~ ~ ~ ~ ~ ~ .,/ O O a) ~J~ 0 al _' ~ ~ ~ ~ O .,4 1 1 C~ ~ ~ ~I ~ I ~ e ~ ~ ~ D D ¢ ^ ~ ~ ~ ~ ~ ~ E~ ~ :~: ~ ~ ~ ~ O O ~ O a) ~ e ~ ~ :^ 3 Cq := O O D hE m- ~ N ~41) c: O JJ 0) N O o U] ,4 O ~ C ~l ~: o C~ o S~ ~O ~D ~ · ~e ~eeee~ O00 ~00 ~00 ~ C ~C~C ~f_ a 1 . - e~ a r~Co ~I~r~ e ~eeeeeee OOOO ~OOO VVV r_~ OO C~ c~u~ e ~ee~ ~C ~f_~ ~r~O ,'_O'O ee ~C: _~_ ~_O JJ . - a' U) ~a e o . - . C) Cd ~ cs cq . U] . - 0 D E O ~C ~C~O ~ ~ ee e ~ee ~· tl) ' ~OC ~ C) - 1 - 1 C~_I ~ -1 U' · ~ - 1 `61 o =1 ~ ~1 c: O S~ I_U ~U~O00 ee eeeeee ~ e C ~;'C~O~o ~0 0 ~S~ ~ C) e ~ O S~ ~ CL a o - U' CO - . e ~ CL a 1 0 0 .,, . - a, 3 C =: ~CO ~e ~ ~ r . ~ tlO . . '-/ a 1 ~O S~ $4 N CN N N ~ eho ' - C~ 6-39 ~ ~;

TABLE 6-5 Binding of [3H]Benzotaipyrene to DNA in Human Endometrial Tissue Taken Throughout Mens trual Cycle and Before and After Menopausea Hormonal S tatus - Early and midproliferative Late proliferative and early secretory Midsecretory and late Premenopausal Postmenopausal cre tory aReprinted with permission from Dorman et al 52 6-40 [3H] B [a]P Binding to DNA, dam/ p~ DNA Mean ~ S.E. 15.0 + 3.69 No. Cases 11 24.5 + 6.12 16 6.7 + 2.12 10 16.8 + 2.70 37 4.7 + 1.67 ~ . me .. ..

TABLE 6-6 Effect of PAHs in Cigarette Smoke on Benzopyrene Hydroxylase Activity in Rat Placentaa PAH Control 1,2-Benzanthracene L, 2,5, 6-Dibenzanthracene 3,4-Benzopyrene Chrysene 3,4-Benzofluorene Anthracene Pyrene Fluoranthene Perylene Phenanthrene 8-Hydroxybenzopyrene formed ng/~-h 218 + 81 4 ~ 034 + 5 19 3 ~ 577 + 494 3 $ 543 + 114 33267 + 117 1, 939 + 98 1, 377 + 3 16 1, 232 + 306 1, 123 + 129 805 + 159 721 + 155 aReprinted with permission from Welch et al.l90 bRats pregnant for 18 d were given PAH orally at 40 mg/kg. Placenta was assayed for benzopyrene hydroxylase activity 21 after the dose. Each value represents the mean + S.E. from three rats. 6-41

TABLE 6-7 Variability in Induction of Benzopyrene Hydroxylase Activity in Human Placentaa Subject L.B. G.A. P.C. C.G. A.T. J.K. L.C. C.J. E.R. D.B. D.A. H.J. M.N. Hydroxybenzopyrene Formed by Placenta, ng / g-h 240 260 547 643 1,269 1,317 1,860 4,289 4,390 . 5,267 15,181 16,524 17,100 aReprinted with permission from Conney et al.42 All subjects in this study were Caucasian, and all smoked 15-20 cigarettes daily during pregnancy. Variability in benzopyrene hydroxylase activity was not related to medication taken during or before delivery. 6-42 ~'. .

PAH 7, 12-Dimethylbenzanthracene Benzo ~ a i pyrene 3-Methy 1 cho lanthrene Dibenz ~ ah janthrac~ne TABLE 6-8 Specific Activities of Binding of Tritium-Labeled PAHs t o Human Branch ia 1 DNAa No . Cases 3 4 2 3 Specific Activity . dpm/llg of DNA pmol/mg of DNA 170_ 22 224_ 77 38 + 9 15 + 3 aReprinted with fission from Harris et al. 70 Nature, Vol. 252, pp. 68-69, copyright 1974 Macmillan Journals Limited. 53_ 7 40 + 14 34 + 8 28 + 6 bMean + S.E. Amount of DNA and dpm determined from peak DNA fraction of CsC1 gradients. 6-43 At; i. _ .

x ~ o to In c) x ~o ~o ~ ~U. e ~He a 3 S ~ be be = o~ ~ 00 a) ¢ Pa ~ I o Z o o N N on Cal 00 0 0 Cad ran ID ~us ~O 00 ~ 00 ~Ad 1 1 1 1 1 1 1 1 1 _ ~00 _ ~_ ~Cad Cal Cal Cad 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ED 0c ~' 3 $~; on o o ~ ~ ~ ~ ~ ~ ~O·eeeeeeee ·~d ~ ~ ;3O ~Cal_ ~us_ o O U. 1 0 000000000 S ~0r ~I_u~ O u:, t0 <: en ¢ E~ :n ~D U~ e ~1 o ~1 I_ ~O _ C ~_ I_ C~ 1 1 1 1 1 1 1 1 c ~u~ u~ 1 u~ OOO OO O O O O C ~_I I_ ~u ~O u~ OU~O OO O O O O I ~d sD C~l - u~ ~^ ~ ~_ ~'_ _ O~O ~~ _ C ~O 0~1-1_ I ~u~\0 6-44 I- E o - U' U) - L~ a rC - 3 ,_ co ~ . - a) ~.....

CJ bO cn 0 e _ 0 1 `4 \0 ~ _ CL ~ e ~o U. ~o c c E e .~d ~S: ~ c ql ~ - 0 0 ~ e ~ ~ ~ 1 1 1 1 1 1~ _ 1 1 ~ r~ o, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 . 1 1 1 1 1 10` 0 1 1 _ _ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~ 1 - ~m- m m - ~ - ~ e ~ ~ e ~ e e ~ ~ ~ e ~ ~ ~ e e ~ e e _ e4 ~ c~ ~ c~ ~ 0 0 ~ O4 0 0 0 c~ ~ ~ ~4 ~ c.4 ~ c~ ~ ~ ~ c4 ~ ~ r~ c~ 40 V V V V V V ~ sD V V 1_ 0 0\ V V V V V V V V V V V V V V V V V V 0 _ L O ~_ c~ - ~I I I I I I I I I I I I I I I _ I 1 1 1- 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 o - ~ t~ _ ~ DO O O O O O O O O O O O O O OO O O O O O O O O O O _ ~ e e ~ ~ e ~ ~ ~ e ~ e ~ e ~ e ~ 0 ~ =) ~ ~ 00 ~ 000000000 ¢' 000 ~ oo 0000 a) 0 ~ N q, V V V V V V V V V V V V V V V _ V V 0 _ ~ V V V V V V V V V OC C V ~O 0` ec' ~_ 0 CL o ~1 _ · - b0 1 1 1 1 ~- 1 ~ 1 1 1 1 1 1 1 1 1 1 1 ~ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 _ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1' 1 1 1 0 ~ 0 CO 0 _1 0 0 0 0O 00 V V V ~ V V V V V V V V V V V O ~ O C~ ~ ~ ~ 0 0 0 0 0 0 ~ a: ~ ~ 0 0 ~ 0 oo ~ a O ~ cr c~ _ ~ bO e _ 0 0 c e ., - ._I or U U U C) U U V {J U 0 ~ ~ ~ ~ ql ~ ~ ~ CJ U U U C) ~ ~ U -^ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~ ql ~ ~ E e 0 0 C ~ ~ _ 6-45 ~o ql bO .. - E~

no c) cd o En - A, - - ~ - o ~ ;a u) a) -~ ofoO oO -~ by~ ~a) a)3 ~·- · -~ ~ E~ ~· ·to ~ ~o so~ · -~ ~o X Cal ~· - ~· ~o . ~_ ~= ~o ·arcO ~ =1 a: ~1 =1 ~O _ O _ 0 1 0 an.·,l up ~up ~ ~0 rid o ~ ~o _ o ~_ Cal_~ ~' '_ _ o -1 1 1 . ~U~o o o ~ ~o ~ 1 1ooO-~;t ~o0 0 oo ~1 1 1 1 1 C~J - c~l ~ ~ ~1 1 1 Cd a; s~ a) u, . . ~_ o ~. ~ ~E a) 0 C ~. ·~q a) ~e e ~e .3 ~I ~- ~, 0 '' ° I ~C ^ ^ E c ~e _ _ ~ ~· - c' ~ - '0 =~- E ~ O ~ ~. - ~. - o o U, UU ~o o o a, 0 cr ~. ~ ~ 1 0 _ 0 · E ~ ~ o · C~ c- ~ o _ ~_~ ~^ - t:L N _' I g - 0 e~a ,0 _ . . 0 ° 1 0 0 0 O 0 1 1 ~ - ~1 1 ' U, e e e 0 0 s" .,1 . cq ~u w ~ o ~ o ~ u' -' ~ ~u) ~· · ~·- · · u, u, o o ~· ~o ~o u, u, · · ~ ~c) e · · ~^ 0 ~o ~ : ~^ 0 a) ~0 ~co ^ ^ b oo oo c ~ a' _ ~° ~n ~- ~s ~ ~ ~0 Q, ~ ~ ~o s ~o ~·- E ~.~ ~.- . r, oc= ~ ~e ~ .- ~0 ~ ~O ~·- 0 ~ ~ oq ~^ t: ^ ~s ~·- 0 0 - ~ 1 ~ 1 ~ ~ ~_ ~0 ~1 0 ~m0 ~ 0 .- ~ ~ ~3 E ~ ~.- s4 ~ ~o ~ ~ ~o c. ~, ~ ~_ ~ ~ 0 ~ ~0 _ 3 ~ C) _ _ ~o ~o o oo ~_ ~ . ·- ·- o ~o ~ ¢ ~x: ~u, ~a c) c' 6-46 ~. . .

1 1 1 0 L' 1 u, ~ c) . - 1 to O ~ ~Q1 cat o ~ ~ o ~ ~ ~ ~ a' c ~ ~ ~ 0 ~x0 x ~ ~ o~ ~ o o a) to X ~ U ·^ ^ ~ a) ct ~1 a cam :^ co X E ~ 1 ~ _ ~ I-, ~=,.,, ~,^ ~.^ o o ~ o ~ ~o ~ ~ ~ ~ .,, ~ ~ ~ ~ ~ lo, ~ o C ~ CO ~ ~ ~ ~ o o ~ ~ ~ o en C o ~ 'c' Cal · ~ ~ ~ ~ ~ ~ CD C · '4 At, ~ o sit o ~ a' ~o 14 u, ~a ~ ~ ~ ~ =.- c~ s" 0 ~ E ° .^e ~ ~ ~ U ~ ~ c O ~41 0 ~ :~- ~ ~ e ~ ca ~ cn ~co ~ ~ ~ ~ ~ o ~ 0 ~ 0 u, ~0 ~ ~ X . ~ ~ ~ == ~ ~ ~ 0 u a) ~ x c ~ x u JJ ~ ~ ~ JJ 0 ~ a) ~E ~ a' ~ ~ ~ ~ ~ ~c' a ~ 0 a) ~ ~ ~ ~ ~ ~ ~ 0 : u ~ a ~a O ~Q)c~ ct O ~ ~ ~ ~ ~ ~ · ^ N ~ ~ a' ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ~ 0 ,4 ~ ~ ~ O ~ me~ ~ U ~ ~ ~ ~O ~ . - ~OC~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ c:c: ~- x ~ x ~ ~ ~ x u ~ ~O x e ~ O ~ u' ~ a) ~ 0 ~ cn E ~ ~ ce co ~Z ~cn ~ a cn o X co o . - o., 1 o _ _ ~ ,1 c' ° .= u' ~ _1 '- ~4 u, c' - o o - a) _4 . - u, o . - o P~ ~, u' u, I ~ ~a) ~. ~1 u' u CO a) ~· u ~ ~U' Ct u: u: U~ ~ ~a) 0 0 0 a) 0 3 ~ t ~c t' ' - ~ ~ 3 ~ . - X u' X ~ t~ Ct ~CO ~ ~s" Q. C ~ ~O 0 u: 0 a'~ ~ ~co ~ ~^ a, c; O 0 u ~ C cn~ ~I ~ ~ e ~ S~= ~.^ ~ .- O ~ ~1 ~ ~ ~ b0 1 ~ ~ ~.^~ e ~- ~O ^ ~ ~ ~ X ~ ~ ~ ~ ~ ~ cn a C) .= O ~ ~ O ~ ~ ^ ~ ~ O ' 1 .,1 ~ ~ a) ~ X cn ~.- ~ ~ c: O C) 1J S ~ a) ~a) 0 ~ ~ ~1 t ~b0 ~ ~ 3 ~ ~ ~c u ~c~ a~ 4~ ct ~ ~ ~ ~1 3 ~ ~ O ~:: e O ~ ~ ~ 3 ;: . ~ ct , ~c~ ~u co ~ X c' ~ ~ ~ -1 a) 0 0 0 u, ct ~c. ~ 0 1 0 cn U) c~ b.0 J_ ~U] ~-4 a,, cn `: ~ ~ ~ O a' ,~ ~ ct ~ e~o ~u, u' ~ a, c' ~ a) ~ ~c: ~ ~cn 0 ~l ~O ~v a) ~ . ~ u' ~0 co c) u: - ~ ~ ·^ X c~ ~ O ~ ~ 6 u~ ct ~u c~ : ~ ,~ ~n ~ 0 ct ~ ~ ~ct ~ ct a ~o a ~ ~ 0 u =~- . c~ ~ SJ ~ ~ c: ' ~ t- ~;t ~-~ J~ $- ~(~} ·-) (~) ~ Ct ~ b0 ~ ' X U~ ~ ~ 0 ~ ~ ~ 0 r~ t~ ~ t: ~ ~ ~t:: cr~ ~ 0 ~/ to s.4 ~1_ ~ 0 C: ~ c~ ~ ~ 0 ~ ~I ce a c~ u, - ~ ~u~ u, 1 ^ ~o ~ oo ~^ -/p ~u) ~Es ~u' ~ ~O u ~c' ~a s~ ~s" ~ O O ~O ~cn ~c oo ~3 0 E u' t4~ ~O ~E s" ~ l_ ~0 O ~Ct ~IJ 1 ~O ~ 1 U) a) ~D 1 ~ ~ ~u O ~c~ ~v b0 0 i4 ~ce ~u' -= ~ ^ O u~ ~0 u ~ ~ ~ 45 ~_d _ - 1 ~ ~ ~ ~u, 0 1 ~ a ~1 ·- ~ 1 a' ~ 0 ~ ~0 ~ 0 co ~ 1 u ~ ~3 ~p: u O E~ ~ S ~c~ ax 3 ~ 3 ~ ~ ~ ~:£ ~c: 6-47 e o o - CO U] - u - 3 . - Q~

l~ l u - u] l rC a) ~ - ~o - ~o u] . - cd o a) O ~: 1 ' o ~o c o c~ - ~u ~c ~u, c,, ~ · a) O Q N U] a) ~ 1 3 P: C~ O O O O O O O O O U] L~ _ O O O O O O 1 - 00 ~ ._ ~CN U' o o o o o C~ C~ O O oo ~_ o o o o o I C~ - 1 1 1 ~o o o O ~- P! ~o C ~· U' ·a ~D Z O ~'- V C: IU] - o a' 1 CO C~ CO =1 ~ C~ ~ I U~ U) 6-48 ··- oC ~ V~4C~ a oo C~C~ 11 u]u) u]u] ·e O~ ~e C~ ~C~ O OO ~d 1 11 u, cqU) o 5- o - U' U' - e s" a' . - 3 ._d

TABLE 6-14 PAHs in Shale Retort Oils,a ppb ComponentParentMethyl-Substituted Pyrene17,50050,500 Fluoranthene5,6508,050 Benz[a]anthracene1,20012,000 Chrysene2,85023,500 Triphenylene5405,700 Benzota~pyrene4,2508,350 Benzoteipyrene1,9502,650 Perylene3251,015 Anthanthrene275455 Benzotghi~perylene1,9008,650 Coronene aReprinted with permission from Weaver and Gibson-187 6-49 it. . .

TABLE 6- 15 PAHs in Drinking Watera Concentration, ng/L Source Mixed tap water at Mainz, Germany Water at :b __ Carc inogenic Total BaP PAH PAH 7.0 Syracuse, NeYo 0 ~ 3 0 ~ 31. 1 Buffalo, N.Y. O .2 0.2O. 9 New York, N.Y. 0.5 3.96.4 Lake George, N.Y. O .3 1.54. 2 Endicott, N.Y. 0.2 1.18.3 . Hammondsport, N.Y 0.3 1.53 . 5 Pittsburgh, Pa. 0.4 1.92.8 Philadelphia, Pa. 0.3 2.014.9 Huntington, W.Va. 0.5 2.07.1 Whee l ing, W. Va. 2 . 1 11.3138 . 5 New Orleans, La. 1.6 1.62.2 Appleton, Wis. 0.4 2.46.1 Champaign, I 1 l . NDC 1. 22 . 8 Fairborn, Ohio 0.1 0.82.9 E lkhart, Ind. NDC O . 30. 3 aReprinted with permission from Santodonato et al.154 bOnly the six W.H.O.-recommended PAHs were analyzed, with the exception that BjF replaced BbF. CND = not detected. 6-50 ~....

PAN TABLE 6-16 PAHs in Tapwatera Naphthalene 2-Methylnaphthalene 1-Methyloaphthalene -Biphenyl Acenaphthene Dibenzofuran Fluorene Dibenzothiophene Phenanthrene Anthracene 2-Methylanthracene 4,5-Methylenephenanthrene l-Methylphenanthrene Fluoranthene Pyrene Benzota~fluorene Benzotbifluorene 4-Methylpyrene Methylpyrene 1-Methylpyrene Benz~aJanthracene Benzo~b~fluoranthene Benzo~jk~fluoranthenes Benzoteipyrene Benzo~a~pyrene aData from Olufsen~l32 Concentration, ppt 2.9 1.4 1.1 0.32 0.82 0. 62 0.72 0.21 3.1 0.35 0.06 0.30 0.37 2. 6 1.1 0.05 0.05 0.05 0.08 0.05 0.49 0.21 0.07 0.20 0.05 6-51 ~.

TABLE 6-17 PAHs in Extracts from Shucked Oystersa Compound Benz 0 [ah i ~ pe rylene Benzo [ a ] pyrene Benz [ a ~ anthracene Benzo [k] f luoranthen Benzo [ e Jpyrene Chrysene Pyrene Fluoranthen~ Approxima te Concentration, g/5 kg of oysters 5-25 10-30 50 40-60 100 100-200 500-800 3, 000-5, 000 aReprinted with permission from Cahnmann and Kurat~une;30 copyright 1957 American Chemical Society . 6-52

TABLE 6- 18 PAHs in Foodstuffsa Concentration, b ~g/kg (wet wt.) Foodstuffs Benzo[a] pyrene Benz anthracene Cooked meats, sausage 0.17-0.63 0.2-1.1 Cooked bacon 1.6-4.2 - Charcoal-broiled meats 2.6-11.2 1.4-31 Smoked ham, sausage Heavily smoked ham (50.4 recorded) 0.02-14.6 0.4-9.6 Up to 23 Up to 12 (107 recorded, Iceland) Cooked fish 0.9 Up to 2.9 Smoked fish 0.3-60 0.02-2.8 (up to 37 in Japan) (up to 189 in Japan) Cereal grains 0.2-4.1 0.4-6.8 Flour and bread 0. 1-4.1 0.4-6.8 Bakers' dry yeast (yeasts 1. 8-40.4 2. 9-93 .5 grown on mineral oils are lower ) Soybean 3!1 - Refined vegetable oils, 0.4-36 - 0.8-1.1 fats Margarine, mayonnaise 0.2-6.8 1.4-29.5 Salad 2.~-12.8 4.6-15.4 Tomatoes 0.2 0.3 Spinach 7.4 16.1 Kale (only 10% removed 12.6-48.1 43. 6-230 by washing) Apples 0.1-0.5 - Fruits (not apples) 2-8 -- Dried prunes 0.2-1.5 - Roasted coffee and 0.1-4 0.5-14.2 - solubles Malt coffee Up to 15 Up to 43 Tea 3.7-21.3 - Whiskey 0.04 ~g/L 0.04-0.08 ~g/L Beer ND ND Roasted peanuts -- Up to 0.95 Milk ND - aReprinted with permission from U.N. Food and Agriculture Organization.180 bND = not detected. 6-53

IC) ~o ~ C~ r~· e e e e e e e e e U] U] U ~U~e - 000000 0 OOZ Z Z ZO ';t ~ 00 °- ~ ~ O ~ie e e e e e U) e e e U] UO CJ) U le O O O O O O Z ° e~ O Z Z Z Z O =1 ~ 1- 00 ~ ~ L~ ~ ~ O ~ O C-1 _4 r ~· e e e e e e e · e e e e (n ~OOOOOOOOOOO~OZ o - ~U o 0 o e.~ · - ~0 5-1 1 1 ~J I~ L~ ~ ~ ~ ~ O ~ ~ O _/ · e U] e U ~ e e e e e cn e U) Cl] ~O O Z O Z O O C~ O O Z ~ Z Z O =1 ^1 c~ ~ ~ a: 0 ~ '~ ~ e e . e e e · e e u~ O ~ ~ C~ ~ ~ U] U. ~ ~ O cn c~ -~ Z Z ~ Z Z C) 0 ~ u~ ~ ~ r_ e e e U] U) e U) e CJ, e e e e cO O O O Z Z ~ Z ~ Z O ~ ~ C~ Z I~ ~a: ~u~ ~ c~ ~e e e e e e e C~ ~ ~ ~ ~ co ~ U) _ ~Z ~ Z C~ Z ~e a) cn . =1 ·~' - ~o o c o c: l ~ Iomc~ ~ £ e e e e e \0 ~ C~ ~ ~ ~ ~ ~ _ O e (,) e C~ ~ U] Z I~ ~ C~ ~ ~ ~ U ~ C~ ~ ~ C~ L ~e e e e e e e e e e e e e C~ ~O ~ ~ J O O ~ -1 ~ t_ ~ ~- _ Z C-l o ~-~ a~ l~ ~ c~ =\ ~ lm e e e e C.) e e e e e U~ ~ ~ 00 ~ O ~ ~ ~ ~ ~ ~ U~ 1- r_ ~_ . ~ =1 ~ =1 Qd ~1 _ U~ ~ ~ ~ U~ CO ~ e e e e C-) e e e e 00 ~ ~C) 00 1- ?_ ~- ~ C-l ~ Ct~ C~ CJO U] ~Z Z Z Z e ~ O e e O ~ ~ O ~ ~ C~ ~ ~ ~ ~ ~ O ~J ~ ~ C~ ~_ ~ C-~ ~ ~ 00 ~ ~ C~ 00 C~ ~ ~ ~ e e e e e e e e e e e O ~ ~ ~ ~ ~ O ~ ~ O O 6-54 o . o . ~o a) e o x · ~ ~o .-d L) a, oc - ~ e r" ~ O - e S" C) U, o . ~e e O o - ~n U' E s~ a' - 3 a) - Q~ ~o s" a) ¢ CO C] a X N . ~:~. :^ o o a) - C' U' o U) a) CO - C) o. - CO ·_I L) oo -_' a) ._1 o 11 Ct cn Z C)

TABLE 6-20 PAHs in Foodsa 1 Anthracene 2 Benz an thracene* 3 Methylbenzanthracene 4 Dibenz~aj~anthracene* 5 Dibenz~ahianthracene* 18 Benzo~j~fluoranthene* 19 8enzo~kifluoranthene 20 Benzotghi~fluoranthene 21 Pyrene 22 4-Methylpyrene 6 Dibenz~ac~anthracene* 23 o-Phenylenepyrene* 7 Dibenz~aiJanthracene* 24 Benzota~pyrene* 8 Phenanthrene 25 Benzote~pyrene* 9 3-Methylphenanthrene 10 2-Methylphenanthrene 11 9-Methylphenanthrene 12 2,6-Dimethylphenanthrene 13 Fluorene 14 Benzota~fluorene 15 Benzotb~fluorene 16 Benzo~a~fluoranthene 17 Benzo~ b ~ f luoran thene 26 Dibenzo~ah~pyrene* 27 Anthanthrene 28 Chrysene* 29 Perylene 30 Benzotghi~perylene 31 Acenaphthene 32 Acenap~thylene 33 2-Methylnaph thalene 34 Naphthalene 35 Acenaphthalene aReprinted with permission from Mix and Schaffer.126 Asterisk indicates known carcinogenicity. 6-55 ~; ~ ,. .. .

TABLE 6-21 PAHs in Foodstuffsa Concentration, Foodstuff Compound /kg Broiled sausage Benz[ajanthracene 0.2-1.1 Smoked sausage 0.4-9.9 Heavily smoked ham 12 Spinach 16 Crude coconut oil 98 Refined vegetable oil 1 Broiled sausage Benzota~pyrene 0.17-0.63 Charcoal-broiled meat 2.6-11.2 Smoked fish 2.1 Spinach 7.4 Tomatoes 0.2 Crude coconut oil 43.7 Roasted coffee 0.1-4 Tea 3.9-21.3 Cereals 0.2-4.1 Smoked ham Benzoteipyrene 5.2 Smoked fish 1.9 Spinach 6.9 Tomatoes 0.2 Crude coconut oil 32.7 Roasted coffee 0.3-7.2 Roasted peanuts 0.4 Broiled sausage Chrysene 0.5-2.6 Heavily smoked ham 21.2 Spinach 28 Tomatoes 0.5 Cereals 0.8-14.5 Roasted coffee 0.6-19.1 Black tea 4.6-6.3 Spinach Tomatoes Cereals aReprinted with permission from Zedeck. 201 6-56 Dibenz [ah] anthracene 0 ~ 3 0*04 0~1-0~6

TABLE 6-22 Benzota~pyrene in Soilsa Benzota~pyrene Origin and Type of Soil Oak forest, West Falmouth, Mass. Pine forest, West Falmouth, Mass. Concentration, ~g/kg 40 40 Mixed forest, West Falmouth, Mass. 1,300 Mixed forest, eastern Conn. Garden soil, West Falmouth, Mass. Plowed field, eastern Conn. 240 90 900 F aReprinted with Permission from M. Blumer, Science 134: 474-475, 1961; 2 copyright 1961 by the American Association for the Advancement of Science. 6-57 ~ . .. . ..

TABLE 6-23 PAHs in Charcoal-Brotled Steaksa PI Alkylbenzanthracene Anthanthrene Anthracene Benz[a]anthracene BenzoEb]chrysene Benzo[ghi]perylene 8enzo[a]pyrene Ben~d[i]pyrene Chrysene Coronene Dibenz[ah]anthracene Eluoranthene Perylene Phenanthrene Pyrene Concentration, pa/kg of steak 2.4 2 4.5 4.5 0.5 4.5 - 8 6 1.4 ~ . ~ 0.2 20 2 11 18 aReprinted with permission from [ijinsky and Shubik.I06 6-58 a-....

c - c~ A: t~ o 0 c ~ e ~ d <e 1 so to d ~ o tic 3 C: o .." to I_ a P. To ~ o o ~ _ 0 C o .- P. sad c c o Cut .= .~ I Cut o ~ UP 0 1 1 1 1 1· · 1 1 1 1 1 1 1 1 1 1 1 1 ups 1 1 1 1 10 0 1 1 1 1 1 1 1 1 1 1 1 1 <s Pe UP 1 1 1 1 1·· 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 100 1 1 1 1 1 1 1 1 1 1 1 1 UP UP 1 1 1 1 1. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~o 1 1 1 1 1 1 1 1 1 1 1 l 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 c ~C C :^ ~' it, 6-59 0

TABLE 6-25 Estimated Daily Human Exposure to PAN from Air, Water, and Fooda Source Benzotaipyrene, fig Total PA, Air . 0.0095-0.0435 0.207 Water 0.0011 0.027 Food 0.16-1.6 1.6-16 aReprinted with permission from Santodonato et al.154 6-60 it ...

70 - 60 as so is 4o 530 20 (O ~m,S~PIIIIIIIIIIIII . lO 15 20 25 50 35 40 SPECI ME N FIGURE 6-1. Spectrum of specific activities of binding of ~ 3H3 to ONA in human endo~netrial tissue in vitro. Human endometrial tissue was incubated for 18 hr in organ culture in medium containing 1 Mt3H)BP. For each of the 41 specimens of endo~netrial tissue examined, specific activities of binding were determined in order to most clearly illustrate the range of binding of [3H] to DNA in endornetrial tissue from these patients. Ellis histogram has been constructed with cases enumerated in increasing order of specific activity. Reprinted with permission from Dorman _ al. 52 \ 6-61 ~.. .

REFERENCE S Ahearn, D. G., S. P. Meyers, and P. G. Standard. The role of yeas ts in the decompos ition of oils in marine environments . Dev. In.d. Microbiol. 12 :126-134, 1971. Alvares, A. P., S. Leigh, A. Kappas, W. Levin, and A. H. Conney. Induction of aryl hydrocarbon hydroxylase in human skin. Drug Metab. Dispos. 1:386-390. 1973. 3. Andelman, J. B., and J. E. Snodgrass. Incidence and signi- ficance of polycyclic aromatic hydrocarbons in the water environment. CRC Crit. Rev. Environ. Control 4:69-83, 1974. 4. Andelman, J. B., and M. J. Suess. Polynuclear aromatic hydro- carbons in the water environment. Bull. W.H.O. 43:479-508, 1970. 5. Anderson, K.-E., A. H. Conney, and A. Kappas. Nutritional influences on chemical biotransformations. Nutr. Rev. 40: 161-171, 1982. Atlas, R. M., and R. Bartha. Abundance, distribution and oil biodegradation potential of microorganisms in Raritan Bay. Environ. Pollut. 4:291-300, 1973. Atlas, S. A., E. S. Vesell, and D. W. Nebert. Genetic control of interindividual variations in the inducibility of aryl hydro carbon hydroxylase in cultured human 1-ymphocytes. Cancer Res. 36:4619-4630, 1976. 8. Aust, A. E., K. J. Falahee, V. M. Maher, and J. J. McCormick. Human cell-mediated benzo~a~pyrene cytotoxicity and mutagenicity in human diploid fibroblasts. Cancer Res. 40: 4070-4075, 1980. 9. Autrup, H., C. C. Harris, G. D. Stoner, M. L. Jesudason, and B. F. Trump. Binding of chemical carcinogens to macromolecules in cultured human colon: Brief communication. J. Natl. Cancer Inst. 59:351-354, 1977. 10. Autrup, H., C. C. Harris, B. F. Trump, and A. M. Jeffrey. Metabolism of benzo~a~pyrene and identification of the major benzota~pyrene-DNA adducts in cultured human colon. Cancer Res. 38:3689-3696, 1978. 11. Autrup, H., R. D. Schwartz, J. M. Essigmann, L. Smith, B. F. Trump, and C. C. Harris. Metabolism of aflatoxin B1 benzotaipyrene, and 1,2-dimethylhydrazine by cultured rat and human colon. Teratog. Carcinog. Mutagen. 1:3-13, 1980. 12. Autrup, H., F. C. Wefald, A. M. Jeffrey, H. Tate, R. D. Schwartz, B. F. Trump, and C. C. Harris. Metabolism of benzota~pyrene by cultured tracheobronchial tissues from mice, rats, hamsters, bovines and humans. Int. J. Cancer 25:293-300, 1980. Avigan, J. The interaction between carcinogenic hydrocarbons and serum lipoproteins. Cancer Res. 19:831-834, 1959. 14. Bailey, E. J., and N. Dungal. Polycyclic hydrocarbons in Icelandic smoked food. Brit. J. Cancer 12:348-350, 1958. 6-62

15. Barfknecht, T. R., B. M. Andon, W. G. Thilly, and R. A. Hites. Soot and mutation in bacteria and human cells, pp. 231-242. In . M. Cooke and A. J. Dennis, Eds. Polynuclear Aromatic Hydrocarbons: Fifth International Symposi.um--Chemical Analysis and Biological Fate. Columbus, Ohio: Battelle Press, 1981. 16. Bast, R. C., T. Okuda, E. Plotkin, R. Tarone, H. J. Rapp, and H. V. Gelboin. Development of an assay to aryl hydrocarbon (benzo~a~pyrene) hydroxylase in human peripheral blood mono- cytes. Cancer Res. 36:1967-1974, 1976. 17. Bast, R. C., Jr., J. P. Whitlock, Jr., H. Miller, H. J. Rapp, and H. V. Gelboin. Aryl hydrocarbon (benzo~a~pyrene) hydroxy- lase in human peripheral blood monocytes. Nature 250:664-665, 1974. ~ 18. Battigelli, M. C., R. J. Mannella, and T. F. Hatch. Environ- mental and clinical investigation of workmen exposed to diesel exhaust in railroad engine houses. Ind. Med. Sorg. 33: 121-124, 1964. 19. Baum, E. J. Occurrence and surveillance of polycyclic aromatic hydrocarbons, pp. 45-70. In H. V. ~elboin and P. O. P. Ts'o, Eds. Polycyclic Aromatic Hydrocarbons and Cancer. Vol. 1. Environment, Chemistry, and MetaboLism. New York: Academic Press, 1978. 20. Berenblum, I., and R. Schoental. Carcinogenic constituents of coal tar. Brit. J. Cancer 1 :157-165, 1947. 21. Bickers, D. R., and A. Kappas. Human skin aryl hydrocarbon hydroxylase. Induction by coal tar. J. Clin. Invest. 62:1061-1068, 1978. 22. Bickers, D. R., A. Kappas, and A. P. Alvares. Differences in inducibility of cutaneous and hepatic drug metabolizing enzymes and cytochrome P-450 by polychlorinated biphenyls and 1,1,1-trichloro-2,2-bis(~-chlorophenyl~ethane (DDT). J. Pharmacol. Exp. Ther. 188:300-309, 1974. 23. Bieri, R. H., V. C. Stemoudis, and M. K. Cuema. Chemical investigations of two experimental oil spills in an estuarine ecosystem, pp. 511-515. In Proceedings--1977 Oil Spill Conference (Prevention, Behavior, Control, Cleanup). Washington, D.C.: American Petroleum Institute, 1977. 24. Biernoth, G., and H. E. Rost. The occurrence of polycyclic aromatic hydrocarbons in coconut oil and their removal. Chem. Ind. 47: 2002-2003, 1967. 25. Blumer, M. Benzpyrenes in soil. Science 134 :474-475, 1961. 26. Brookes, P., and M. E. Duncan. Carcinogenic hydrocarbons and human cells in culture. Nature 234:40-43, 1971. 27. Buening, M. K., R. L. Chang, M-T. Huang, J. G. Fortner, A. W. Wood, and A. H. Conney. Activation and inhibition of benzo~a~pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids. Cancer Res. 41: 67-72, 1981. 28. Buening, M. K., J. G. Fortner, A. Kappas, and A. H. Conney. 7,8-Benzoflavone stimulates the metabolic activation of aflatoxin B1 to mutagens by human liver. Biochem. Biophys. Res. Commun. 82:348-355, 1978. 6-63 ~;

29. Busbee, 3. L.; C. R. Shaw, and E. T. Cantrell. Aryl hydrc- carbon hydroxylase induction in human leucocytes. Science 178: 315-316, 1972. 30. Cahn~nan~, H. J., and M. Kuratsune. Determination of polycyclic aromatic hydrocarbons in oysters collected in polluted water. Anal . Chern. 29 :1312-1317 , 1957. 31. Charlton, S. C., J. S. Olson, K-Y. Hong, H. J. Pownall, D. 13. Louie, and L. C. Smith. Stopped flow kinetics of pyrer~e trans Eer between human high density lipoproteins. J. Biol. Chem. 251: 7952-7955, 1976. 32. Chen, T. C., W. A. Bradley, A. M. Gotto, Jr., and J. D. Morrisett. Binding of the chemical carcinogen p-dimethyl aminoszoSenzene by human plasma low density lipoproteins. FEB Lett. 104: 236-240, 1979. Chevion, M., J. J. Stegeman, J. Peisach, and W. E. Blumberg. Electron paramagne tic resonance studies on bepatic ~nicrosomal cytoc`~rome P450 from a marine teleost fish. Life Sci. 20: 895-900 ~ 197 7. 34. Coher~, G. M., S. >1. Haws, B. P. Moore, and J. W. Bridges. Benzo~a) pyren-3-yl hydrogen sulphate, a ma jor ethyl acetate extractable metabolite of 7'enzo~a~pyrene in human, hamster and rat lung cultures. Biochem. Pharmacol. 25: 2561-2570, 1976. 35. Cohen, G. M., R. Meh ta , and M. M. Brown. Large interindividual variat: ions in m``eta~olis;r1 ~f benzo~a~pyrene by peripheral tuna tisswe fro~r. '~ ung cancer patients. Int. J. Cancer 24:129-133, 1979. 36. Cor~norer, t-., .~. J. Vithyathil, P. Dolara, S. llair, P. bladyastha, and G. C. Cuca. Formation of mutagens in beef and beef extract ~uring cooking. Science 201:913-916, 1978. Connell, D. W., and G. J. Miller. Petroleum hydrocarbons in aquatic ecosystems--behavior and effects of sublethal concentra tio-.~s: Part L. CRC Crit. Rev. Environ. Control 17 :37-104, 1981. Ccr~ne7l, O. W., and G. J. Miller. Petroleum hydrocarbons in aquatic ecosystems--behavior and effects of sublethal concentrations: Part 2. C2C Crite Rev. Environ. Control 11:105-162, 1981. Conney, A. H., M. K. Buening, E. J. Pantuck, C. B. Pantuck, J. G. Fortner, K. E. Anderson, and A. Kappas. Regulation of human drug m.etabolism by dietary factors. Ciba Found. 76:147-167, 1980. Conney, A. H., and W. Levin. Carcinogen ~netabolism in experi mental aniT.nals and man, pp. 3-22. In R. Montesano, L. Tomatis, ar~d W. Davis, Eds. Chemical Carcinogenesis Essays. IARC Scientific Publication No. 10. Lyon, France: Interr~ational Agency for Research on Cancer, 1974. Conney, A. H., E. J. Pantuck, C. B. Pantuck, M. Buening, D. M. Jerina, J. G. Fortner, A. P. Alvares, K. E. Anderson, and A. Kappas. Role of environment and diet in the regulation of buman drug metabolism, pp. 583-605. In R. N. Estabrook and E. Lindenlaub, Eds. The Induction of Drug Metabolism. New York: F. K. .Schattauer Verlag, 1978. 33. 37. 38. 39. 40. 41. 6-64

42. Conney, A. H., R. Welch, R. Kuntzman, R. Chang, M. Jacobson, A. D. Munro-Faure, A. W. Peck, A. Bye, A. Poland, P . J . Poppers, M. Finster, and J. A. Wolff. Effects of environmental chemicals on the metabolism of drugs, carcinogens, and normal body con stituents in man. Ann. N.Y. Acad. Sci. 179:155-172, 1971. 43. Cook, J. W., C. R. Hewett, and I. Hieger. The isolation of a cancer-producing hydrocarbon from coal tar. Parts I, II, and III . J . Chem. Soc . I, Part I: 395-405, 1933. 44. Corner, E. D. S., R. P. Harris, K. J. Whittle, and P. R. Mackie. Hydrocarbons in marine zooplankton and fish, pp. 71-106. In A. P. M. Lockwood, Ed. Effects of Pollutants on Aquatic Organisms. Cambridge, Eng. : Cambridge University Press, 1976. 45. Cottini, G. B., and G. B. Mazzone. The effects of 3:4 benz pyrene on human skin. Amer. J. Cancer 37 :186-195, 1939. 46. TOawe, C. J., O. G. Scarpelli, and S. R. Wellings, Eds. Tumors in Aquatic Animals. (Progress in Experimental Tumor Research, Vol. 20. ~ Basel: S. Karger, 1976. 438 pp. 47. Devereux, T. R., C. J. Serab jit-Singh, S. R. Slaughter, C. R. Wolf, R. M. Philpot, and J. R. Fouts. Identification of cytochrome P-450 isozymes in conciliated bronchiolar epithelial (Clara) and alveolar type II cells isolated from rabbit lung. Exp. Lung Res. 2:221-230, 1981. 48. Dewaide, J. H. Species differences in hepatic drug oxidation mammals and fishes in relation to thermal acclimation. Comp. Gen. Pharmacol. 1:375-384, 1970. 49. Dewaide, J. H., and D. T. Henderson. Seasonal variation of hepatic drug metabolism in roach, Leuciscus-Rutilus L. Comp. Biochem. Physiol. 32:489-498, 1970. 50. Dietz, M. H., and B. A. Flaxman. Toxicity of aromatic hydro- carbons on normal buman epidermal cells ~n vitro. Cancer Res. 31:1206-1209, 1971. 51. DiSalvo, L. H., and H. E. Guard. Hydrocarbons associated with suspended particulate matter in San Francisco Bay waters, pp. 169-173. In 1975 Conference on Prevention and Control of Oil Pollution--Proceedings. Washington, D.C.: American Petroleum Institute, 1975. 52. Dorman, B. H., V. M. Genta, M. J. Mass, and D. G. Kaufman. Benzo~a~pyrene binding to DNA in organ cultures of human endo- metrium. Cancer Res. 41:2718-2722, 1981. Dunn, B. P., and H. F. Stich. Release of the carcinogen benzo~a~pyrene from environmentally contaminated mussels. Bull. Environ. Contam. Toxicol. 15:398-401,1976. 54. Dybing, E., C. von Bahr , T. Aune, H. Glaumann, D. S. Levitt, and S. S. Thorgeirsson. In vitro metabolism and activation of - carcinogenic aromatic amines by subcellular fractions of buman 1iver. Cancer Res. 39:4206-4211, 1979. 55. E1 Batawi, M. A., and M. H. Noweir. Health problems resulting from prolonged exposure to air pollution in diesel bus garages. Ind. Heal th 4 :1-10 , 1966. 56. Falk, H. L., P. Kotin, and I. Markul. The disappearance of carcinogens from soot in buman lungs. Cancer 11:482-489, 1958. 53. 6-65 . -

61 62. 63. 64. 57. Falk, H. L., A. Miller, and P. Kotin. Elution of 3,4-benz pyrene and related hydrocarbons from soots by plasma proteins. Science 127:474-475, 1958. Fisher, A. B., G. A. Huber, and L. Furia. Cytochrome P450 con tent and mixed funct ion oxidation by microsomes from rabbit alveolar macrophases. J. Lab. Clin. Med. 90:101-108, 1977. 59. Folinsbee, L. J., J. F. Bedi, and S. M. Horvath. Respiratory responses in humans repeatedly exposed to low concentrations of ozone. Amer. Rev. Respir. Dis. 121:431-439, 1980. 60. Freeman, A. E., R. S. Lake, H. J. Igel, L. Gernand, M. R. Pezzutti, J. M. Malone, C. Mark, and W. F. Benedict. Heteroploid conversion of human skin cells by methylcholanthrene: Possible role of hydrocarbon metabolizing epithelial cells, pp. 100-122. In U. Saffiotti and H. Autrup, Eds. In Vitro Carcinogenesis: Guide to the Literature, Recent Advances and Laboratory Procedures. Carcinogenesis Tech. Rept. Ser. No. 44, National Cancer Institute NCI-CG-TR-44. OHEW Publ. No. (NIH)78-884. Washington, D.C.: U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, 1978. Gerhart, E. H., and R. M. Carlson. Hepatic mixed-function oxidase activity in rainbow trout exposed to several polycyclic aromatic compounds. Environ. Res. 17:284-295, 1978. Goeckerman, W. H. The treatment of psoriasis. Northwest Med. 24:229-231, 1925. Goeckerman, W. H. Treatment of psoriasis: continued observa tions on the use of crude coal tar and ultraviolet light. Arch. Dermatol. Syphilol. 24:446-450, 1931. Gray, J. I., and I. D. Morton. Some toxic compounds produced in food by cooking and processing. J. Hum. Nutr. 35:5-23, 1981. 65. Grimmer, G., and A. Hildebrandt. Concentration and estimatation of 14 polycyclic aromatic hydrocarbons at low levels in high- protein foods, oils and fats. J. Assoc. Offic. Anal. Chem. 55:631-635, 1967. 66. Grover, P. L., A. D. MacNicoll, P. Sims, G. C. Easty, and A. M. Neville. Polycyclic hydrocarbon activation and metabolism in epithelial cell aggregates prepared from human mammary tissue. Int. J. Cancer 26:467-475, 1980. 67. Haenni, E. O. Analytical control of polycyclic aromatic hydro- carbons in food and food additives. Residue Rev. 24:41-78, 1968. 68. Harris, C. C., H. Autrup, G. D. Stoner, B. F. Trump, E. Hillman, P. W. Schafer, and A. M. Jeffrey. Metabolism of benzota)- pyrene, N-nitrosodimethylamine, and N-nitrosopyrrolidine and identification of the major carcinogen-DNA adducts formed in cultured human esophagus. Cancer Res. 39:4401-4406, 1979. 69. Harris, C. C., H. Autrup, G. Stoner, S. K. Yang, J. C. Leutz, H. V. Gelboin, J. K. Selkirk' R. J. Conner, L. A. Barrett, R. T. Jones, E. McDowell, and B. F. Trump. Metabolism of benzo~a)- pyrene and 7,12-dimethylbenz~aJanthracene in cultured h~man bronchus and pancreatic duct. Cancer Res. 37:3349-3355, 1977. 6-66

70. Harris, C. C., V. M. Genta, A. L. Frank, D. G. Kaufman, L. A. Barrett, E. M. McDowell, and B. F. Trump. Carcinogenic poly- nuclear hydrocarbons bind to macromolecules in cultured human bronchi. Nature 252:68-69, 1974. 70a. Harris, C. C., I. C. Hsu, and G. D. Stoner. Human pulmonary alveolar macrophages metabolize benzo~a~pyrene to proximate and ultimate mutagens. Nature 272:633-634, 1978. 71. Hook, G. E. R., J. R. Bend, and J. R. Fouts. Mixed-function oxidases and the alveolar macrophage. Biochem. Pharmacol. 21: 3267-3277, 1972. 72. Hsu, I. C., G. D. Stoner, H. Autrup, B. F. Trump, J. K. Selkirk, and C. C. Harris. Human bronchus-mediated mutagenesis of mammalian cells by carcinogenic polynuclear aromatic hydro- carbons. Proc. Natl. Acad. Sci. USA 75:2003-2007, 1978. 73. Huang, M.-T., R. L. Chang, J. G. Fortner, and A. H. Conney. Studies on the mechanism of activation of microsomal benzo~a]- pyrene hydroxylation by flavonoids. J. Biol. Chem. 256:6829- 6836, 1981. 74. Hussain, M. Z., S. D. Lee, and R. S. Bhatnagar. Increased aryl hydrocarbon hydroxylase and prolyl hydroxylase activities in lung organ cultures exposed to benzo~aipyrene. Toxicology 12: 267-271, 1979. 75. Jeffrey, A. M., I. B. Weinstein, K. W. Jennette, K. Grzeskowiak, K. Nakanishi, R. G. Harvey, H. Autrup, and C. Harris. Structures of benzo~a~pyrene-nucleic acid adducts formed in human and bovine bronchial explants. Nature 269: 348-350, 1977. 76. Juchau, M. R., J. A. Bond, and E. P. Benditt. Aryl 4 ~ono- oxygenase and cytochrome P-450 in the aorta: Possible role in atherosclerosis. Proc. Natl. Acad. Sci. USA 73:3723-3725, 1976. 77. Juchau, M. R., J. A. Bond, R. M. Kocan, and E. P. Benditt. Bioactivation of polycyclic aromatic hydrocarbons in the aorta: Evidence for a role in the genesis of atherosclerotic lesions, pp. 639-652. In P. W. Jones and P. Leber, Eds. Polynuclear Aromatic Hydrocarbons: 3rd International Symposium on Chemistry and Biology--Carcinogenesis and MuLagenesis. Ann Arbor, Mich.: Ann Arbor Science Publishers, 1979. 78. Kahng, M. W., M. W. Smith, and B. F. Trump. Aryl hydrocarbon hydroxylase in human bronchial epithelium and blood monocyte. J. Natl. Cancer Inst. 66:227-232, 1981. 79. Kakunaga, T. Neoplastic transformation of human diploid fibro- blast cells by chemical carcinogens. Proc. Natl. Acad. Sci. USA 75:1334-1338, 1978. 80. Kapitulnik, J., W. Levin, A. Y. H. Lu, R. Morecki, P. M. Dansette, D. M. Jerina, and A. H. Conney. Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes. Clin. Pharmacol. Ther. 21:158-165, 1977. 81. Kapitulnik, J., P. J. Poppers, M. K. Buening, J. G. Fortner, and A. H. Conney. Activation of monooxygenases in human liver by 7,8-benzoflavone. Clin. Pharmacol. Ther. 22:475-484, 1977. 82. Kapitulnik, J., P. J. Poppers, and A. H. Conney. Comparative metabolism of benzo~a~pyrene and drugs in human liver. Clin. Pharmacol. Ther. 21:166-176, 1977. 83. Kaplan, I. Relationship of noxious gases to carcinoma of the lung in railroad workers. J.A.M.A. 171:2039-2043, 1959. 6-67 ~; ~ . .. . ..

84. Kappas, A., A. P. Alvares, K. E. Anderson, E. J. Pantuck, C. B. Pantuck, R. Chang, and A. H. Conney. Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Clin. Pharmacol. Ther. 23:445-450, 1978. 85. Kellermann, G., M. Luyten-Kellermann, M. G. Horning, and M. Stafford. Elimination of antipyrine and benzotaipyrene metabolism in cultured human lymphocytes. Clin. Pharmacol. Ther. 20:72-80, 1976. 86. Kellermann, G., M. Luyten-Kellenmann, and C. R. Shawl Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes. Amer. J. Hum. Genet. 25:327-331, 1973. 87. Kellermann, G., C. R. Shaw, and M. Luyten-Kellermann. Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. New Eng. J. Med. 289:934-937, 1973. 88. Kennaway, R. The identification of a carcinogenic compound in coal-tar. Brit. Med. J. 2:749-752, 1955. 89. Kolar, L. Contamination of soils and agricultural crops with the carcinogenic 3,4-benzopyrene and its causes. Rostl. Vyroba 21:261-269, 1975. 90. Kopelovich, L., N. E. Bias, and L. Helson. Tumour promoter alone induces neoplastic transformation of fibroblasts from bumans genetically predisposed to cancer. Nature 282:619-621, 1979. 91. Kouri, R. E., C. E. McKinney, D. J. Slomiany, D. R. Snodgrass, N. P. Wray, and T. L. McLemore. Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes. Cancer Res. - 42:5030-5037, 1982. 92. Kouri, R. E., J. Oberdorf, D. J. Slomiany, and C. Eo McKinney. A method for detecting aryl hydrocarbon hydroxylase activities cryopreserved human lymphocytes. Cancer Lett. 14:29-40, 1981. 93. Kraybill, H. F., C. J. Dawe, J. C. Harshbarger, and R. G. Tardiff, Eds. Aquatic Pollutants and Biological Effects with Emphasis on Neoplasia. Ann. N.Y. Acad. Sci. 298:1-604, 1977. 94. Kuntzman, R., L. C. Mark, L. Brand, M. Jacobson, W. Levin, and A. H. Conney. Metabolism of drugs and carcinogens by buman liver enzymes. J. Pharmacol. Exp. Ther. 152:151-156, 1966. 95. Lake R. S., M. L. Kropko, M. R. Pezzutti, R. H. Shoemaker, and H. J. Igel. Chemical induction of unscheduled DNA synthesis in human skin epithelial cell cultures. Cancer Res. 38: 2091-2098, 1978. 96. Lake, R. S., M. R. Pezzutti, M. L. Kropko, A. E. Freeman, and H. J. Igel. Measurement of benzo~a~pyrene metabolism in human monocytes. Cancer Res. 37:2530-2537, 1977. 97. Lakowicz, J. R., and D. R. Bevan. Effects of asbestos, iron oxide, silica, and carbon black on the microsomal availability of benzo~a~pyrene. Biochemistry 18:5170-5176, 1979. 98. Lakowicz, J. R., and J. L. Hylden. Asbestos-mediated membrane uptake of benzo~a~pyrene observed by fluorescence spectroscopy Nature 275:446-448, 1978. 6-68 ~ . . .. .

99. Lakowicz, J. R., J. L. Hylden, F. Englund, A. Hidmark, and McNamara. Asbestos-facilitated membrane uptake of polynuclear aromatic hydrocarbons studied by fluorescence spectroscopy: A possible explanation of the cocarcinogenic effects of particulates and PAR, pp. 835-853. In P. W. Jones and P. Leber, Eds. Polynuclear Aromatic Hydrocarbons. Ann Arbor, Mich.: Ann Arbor Science Publishers, Inc., 1979. 100. Lasker, J. M., M.-T. Huang, and A. H. Conney. In vivo activation of zoxazolamine by flavone. Science 216:1419-1421, 1982. 101. Lee, R. F., W. S. Gardner, J. W. Anderson, J. W. Blaylock, and J. Barwell-Clarke. Fate of polycyclic aromatic hydrocarbons in controlled ecosystem enclosures. Environ. Sci. Technol. 12:832-838, 1978. 102. Lee, R. F., C. Ryan, and M. L. Neuhauser. Fate of petroleum hydrocarbons taken up from food and water by the blue crab Call~nectes sapidus. Marine Biol. 37:363-370, 1976. 103. Levin, W., A. H. Conney, A. P. Alvares, I. Merkatz, and A. Kappas. Induction of benzota~pyrene hydroxylase in human skin. Sc fence 176 : 419-420, 197 2 . 104. Li jinsky, W., and A. E. Ross. Production of polynuclear hydro carbons in the cooking of foods. Food Cosmet. Toxicol. 5:343 347, 1967. 105. Lijinsky, W., and D. Shubik. Benzo~a~pyrene and other polynuclear hydrocarbons in charcoal broiled steaks. Science 145:53-55, 1964. 106. Lijinsky, W., and P. Shubik. Polynuclear hydrocarbon carcinogens in cooked meat and smoked food. Ind. Med. Surg. 34:152-154, 1965. 107. Lijinsky, W., and D. Shubik. The detection of polycyclic aromatic hydrocarbons in liquid smoke and some foods. Toxicol. Appl. Pharm. 7:337-343, 1965. 108. Lloyd, J. W. Long-term mortality study of steelworkers. V. Resp~ratory cancer in coke plant workers. J. Occup. Med. 13: 53-68, 1971. 109. Lloyd, J. W., F. -E. Lundin, Jr., C. K. Redmond, and P. B. Geiser. Long term mortality study of steelworkers. IV. Mortality by work area. J. Occup. Med. 12:151-157, 1970. 110. Ma, J. K. H., P. P. Fu, and L. A. fuzz). Protein binding of benz~aJanthracene and benzota~pyrene. J. Pharm. Sci. 66:209-213, 1977. 111. Maines, M. D., and A. Kappas. The degradative effects of porphyrins and heme compounds on components of the microsomal mixed function oxidase system. J. Biol. Chem. 250:2363-2369, 1975. 112. Malonoski, A. J., E. L. Greenfield, C. J. Barnes, J. M. Worthington, and F. L. Joe, Jr. Survey of polycyclic aromatic hydrocarbons in smoked foods. J.A.O.A.C. 51:114-121, 1968. 1 13 . Mas s , M. J . , N. T. Rodgers , and D. G. Kaufman. Benzo [ a ] pyrene metabolism in organ cultures of human endometrium. Chem. Biol. Interact. 33:195-205, 1981. 6-69 ~;

l 114. Masuda, Y., and M. Kuratsune. Polycyclic aromatic hydrocarbons in smoked fish, "katsuobushi." Gann. 62:27-30, 1971. L15. Masuda, Y., K. Mori, and M. Kuratsune. Polycyclic aromatic hydrocarbons formed by pyrolysis of carbohydrates, amino acids and fatty acids. Gann. 58:69-74, 1967. 116. Matsumoto, T., D. Yoshida, S. Mizusaki, and H. Okamoto. Mutagenic activity of amino acid pyrolyzates in Salmonella typhimurium TA 98. Mutat. Res. 48:279-286, 1977. 17. Mazumdar, S., C. Redmond, W. Sollecito, and N. Sussman. An epidemioLogical study of exposure to coal tar pitch volatiles among coke oven workers. J. Air Pollut. Control Assoc. 25: 382-389, 1975. 118. McCain, B. B., H. O. Hodgkins, W. D. Gronlund, J. W. Hawkes, D. W. Brown, M. S. Myers, and J. H. Vandermeulen. Bioevail- ability of crude oil from experimental oil sediments to English sole (Parophyrup vetulus) and pathological consequences . J. Fish. Res O Board Can. 35:657-664, 1978. 119. McLemore, T. L., and R. R. Martin. Pulmonary carcinogenesis: Aryl hydrocarbon hydroxylase, pp. 3-54. In R. B. Livingston, Ed. Lung Cancer: Advances in Research and Treatment. The Hague, The Netherlands: Martinus Nijhoff Publishers, 1981. 120. McLemore, T. L., R. R. Martin, D. L. Busbee, R. C. Richie, R. R. Springer, K. L. Toppell, and E. T. Cantrell. Aryl hydrocarbon hydroxylase activity in pulmonary macrophages and lymphocytes from lung cancer and non-cancer patients. Cancer Res. 37: 1175-1181, 1977. 121. McLemore, T. L., R. R. Martin, L. R. Pickard, R. R. Springer, N. P. Wray, K. L. Toppell, K. L. Mattox, G. A. Guinn, E. T. Cantrell, and D. L. Busbee. Analysis of aryl hydrocarbon hydroxylase activity in human lung tissue, pulmonary macrophages, and blood lymphocytes. Cancer 41:2292-2300, 1978. 122. McLemore, T. L., R. R. Martin, N. P. Wray, E. T. Cantrell, and D. L. Busbee. Di-sassociation between aryl hydrocarbon hydroxylase activity in cultured pulmonary macrophages and blood lymphocytes from lung cancer patients. Cancer Res. 38:3805-3811, 1978. 123. Milo, G. E., J. Blakeslee, D. S. Yohn, and J. A. DiPaolo. Biochemical activation of aryl hydrocarbon hydroxylase activity, cellular distribution of polynuclear hydrocarbon metabolites, and DNA damage by polyouclear hydrocarbon products in human cells in vitro. Cancer Res. 38:1638-1644, 1978. 124. Milo, G. E., Jr., and J. A. DiPaolo. Neoplastic transformation of human diploid cells ~n vitro after chemical carcinogen treatment. Nature 275:130-132, 1978. 125. Milo, G. E., and J. A. DiPaolo. Presensitization of human cells with extrinsic signals to induced chemical carcinogenesis. Int. J. Cancer 26:805-812, 1980. 126. M~x, M. C., and R. L. Schaffer. Benzo~a~pyrene concentration in mussels (Mytilus edulis) from Yaquina Bay, Oregon during June 1976-May 1978. Bull. Environ. Contam. Toxicol. 23:677-684, 1979. 6-70 ~. '.

139. 127. Nagao, M., M. Honda, Y. Seino, T. Yahagi, and T. Sugimura. Mutagenicities of smoke condensates and the charred surface of fish and meat. Cancer Lett. 2:221-226, 1977. 128. Namkung, M. J., and M. R. Juchau. On the capacity of human placental enzymes to catalyze the formation of dials from benzotaipyrene. Toxicol. Appl. Pharmacol. 55:253-259, 1980. 129. Neff, J. M. Polycyclic Aromatic Hydrocarbons in the Aquatic Environment: Sources, Fates and Biological Effects. London: Applied Science Publishers, Ltd., 1980. 262 pp. 130. Obana, H., S. Hori, T. Kashimoto, and N. Kunita. Polycyclic aromatic hydrocarbons in human fat and liver. Bull. Environ. Contam. Toxicol. 27:23-27, 1981. 131. Okuda, T., E. S. Vesell, E. Plotkin, R. Tarone, R. C. Bast, and H. V. Gelboin. Interindividual and intraindividual variations in aryl hydrocarbon hydroxylase in monocytes from monozygotic and dizygotic twins. Cancer Res. 37:3904-3911, 1977. 132. Olufsen, B. Polynuclear aromatic hydrocarbons in Norwegian drinking water sources, pp. 333-343. In Ae Bjorseth and A. J. Dennis, Eds. Polynuclear Aromatic Hydrocarbons: Chemistry and Biological Effects. Proceedings of the 4th International Symposium. Columbus, Ohio: Battelle Press, 1981. 133. Paigen, B., H. L. Gurtoo, J. Minowada, L. Houten, R. Vincent, K. Paigen, N. B. Parker, E. Ward, and N. T. Hayner. Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk. New Eng. J. Med. 297:346-350, 1977. 134. Paigen, B., H. L. Gurtoo, E. Ward, J. Minoweada, L. Houten, R. Vincent, N. B. Parker, and J. Vaught. Human~aryl hydrocarbon hydroxylase and cancer risk, pp. 429-438. In P. W. Jones and R. J. Freudenthal, Eds. Carcinogenesis. Vol. 3. Polynuclear Aromatic Hydrocarbons. New York: Raven Press, 1978. 135. Painter, R. B. Rapid test to detect agents that damage human DNA. Nature 265:650-651, 1977. 136. Pantuck, E. J., K-C. Hsiao, A. H. Conney, W. A. Garland, A. Kappas, and K. E. Anderson. Effect of charcoal-broiled beef on phenacetin metabolism in man. Science 194:1055-1057, 1976. Pantuck, E. J., K-C. Hsiao, R. Kuntzman, and A. H. Conney. Intestinal metabolism of phenacetin in the rat--Effect of charcoal-broiled beef and rat chow. Science 187:744-746, 1975. 138. Pelkonen, O., N. T. Karki, P. Korhonen, M. Koivisto, R. Tuimala, and A. Kauppila. Human placental aryl hydrocarbon hydroxylase: Genetics and environmental influences, pp. 765-777. In P. W. Jones and P. Leber, Eds. Polynuclear Aromatic Hydrocarbons. Third International Symposium on Chemistry and Biology--Carcinogenesis and Mutagenesis. Ann Arbor, Mich.: Ann Arbor Science Publishers, Inc ? 1979. Pelkonen, O., and H. Saarni. Unusual patterns of benzota~pyrene metabolites and DNA-benzota~pyrene adducts produced by human placental microsomes ~n vitro. Chem. Biol. Interact. 30: 287-296, 1980. 6-71 ..-- ....

140. Philpot, R. M., M. O. James, and J. R. Bend. Metabolism of benzota~pyrene and other xenobiotics by microsomal mixed- function oxidases in marine species, pp. 184-199. In Sources, Effects and Sinks of Hydrocarbons in the Aquatic Environment. Proceedings of the Symposium, American University, Washington, D.C. , 9-11 August 1976. Arlington, Va.: American Institute of Biological Sciences, 1976. 141. Pike, M. C., and B. E. Henderson. Epidemiology of polycyclic hydrocarbons: Quantifying the cancer risk from cigarette smoking and air pollution effects, pp. 317-334. In H. V. Gelboin and P. O. P. Ts'o, Eds. Polycyclic Hydrocarbons and Cancer. Vol. 3. New York: Academic Press, Inc., 1981. 142. Pott, P. Chirurgical observations relative to the cataract, the polypus of the nose, the cancer of the scrotum, the different kinds of ruptures, and the mortification of the toes and feet. London: Hawes [and others], 1775. 208 pp. Prough, R. A., V. W. Patrizi, R. T. Okita, B. S. Masters, and S. W. Jackobsson. Characteristics of benzo~a~pyrene metabolism by kidney, liver, and lung microsomal fractions from rodents and humans. Cancer Res. 39:1199-1206 5 1979. 144. Prough, R. A., Z. Sipal, and S. W. Jakobsson. Metabolism of benzota~pyrene by human lung microsomal fractions. Life Sci. 21:1629-1636, 1977. 145. Ptashne, K., L. Brothers, S. G. Axline, and S. N. Cohen. Aryl hydrocarbon hydroxylase induction in mouse peritoneal macro- phages and blood-derived human macrophages. Proc. Soc. Exp. Biol. Med. 146:585-589, 1974. 146. Rappaport, S. M., M. C. McCartney, and E. T. Wei. Volatiliza- tion of mutagens from beef during cooking. Cancer Lett. 8: 139-145, 1979. 147. Reger, R. B., J. L. Hankinson, and J. A. Merchant. Ventilatory Function Changes Over a Work Shift for Coal Miners Exposed to Diesel Emissions, pp. 1-23. Morgantown, W. Va.: Appalachian Laboratory for Occupational Safety and Health, National Institute for Occupational Safety and Health. (undated) (draft) 148. Reid, W. D., J. M. Glick, and G. Krishna. ~0 compounds by alveolar macrophages of rabbits. Biochem. Biophys. Res. Commun. 49:626-634, 1972. 149. Remsen, J. F., and R. B. Shireman. . . . Metabolism ~ f f~r~ i en Effect of low-density lipo proce~n on tue ~ncorporation of benzo~a~pyrene by cultured cells. Cancer Res. 41:3179-3185, 1981. 1500 Rhee, K. S., and L. J. Bratzler. Polycyclic hydrocarbon composition of wood smoke. J. Food Sci. 33:626-632, 1968. 151. Rice, J. M. An overview of transplacental chemical carcino- genesis. Teratology 8:113-125, 1973. 152. Royal College of Physicians of London, Committee on Smoking and Atmospheric Pollution. Air Pollution and Health: Summary and Report on Air Pollution and its Effect on Health by the Committee of the Royal College of Physicians of London on Smoking and Atmospheric Pollution, pp. 48-57. London: Pitman Medical and Scientific Publishing Co., 1970. 6-72 a;~~ _. .

153. Sabadie, N., H. B. Richter-Reichhelm, R. Saracci, U. Mohr, and H. Bartsch. Inter-individual differences in oxidative benzo~a)- pyrene metabolism by normal and humorous surgical lung specimens from 105 lung cancer pat tents. Int. J. Cancer 27:417-425, 1981. 154. Santodonato, J., P. Howard, and D. Basu. Health and Ecological Assessment of Polynuclear Aromatic Hydrocarbons. J. Environ. Pathol. Toxicol. (Special Issue) 5~1~:1-366, 1981. 155. Schenker, M. B. Diesel exhaust--an occupational carcinogen? J. Occup. Med. 22:41-46, 1980. 156. Schlede, E., R. Kuntzman, and A. H. Conney. Stimulatory effect of benzo~a~pyrene and phenobarbital pretreatment on the biliary excretion of benzo~a~pyrene metabolites in the rat. Cancer Res. 30:2898-2904, 1970. 157. Schlede, E., R. Kuntzman, S. Haber, and A. H. Conney. Effect of enzyme induction on the metabolism and tissue distribution of benzo~a~pyrene. Cancer Res. 30:2893-2897, 1970. 158. Schonwald, A. D., C. R. Bartram, and H. W. Rudiger. Benzpyrene- induced sister chromatic exchanges in lymphocytes of patients with lung cancer. Hum. Gene t. 36:261-264, 1977. 159. Seidel, K., and H. Happel. Effect o~f refuse compost on 3,4- benzopyrene content in carrots and head lettuce. Naturwiss- enschaften 62:300, 1975. 160. Selkirk, J. K., R. G. Croy, J. P. Whitlock, Jr., and H. V. Gelboin. In vitro metabolism of benzo~a~pyrene by human liver microsomes and lymphocytes. Cancer Res. 35:3651-3655, 1975. 161. Shinohara, K., and P. A. Cerutti. Formation of benzota~pyrene- DNA adducts in peripheral human lung tissue. Cancer Lett. 3: 303-309, 1977. 162. Shu, H. P., and A. V. Nichols. Benzo~a~pyrene uptake by human plasma lipoproteins tn vitro. Cancer Res. 39:1224-1230, 1979. 163. Smith, L. C., and M. C. Doody. Kinetics of benzota~pyrene transfer between human plasma lipoproteins, pp. 615-624. In M. Cooke and A. J. Dennis, Eds. Chemical Analysis and Biological Fate: Polynuclear KAromatic Hydrocarbons. 5th International Symposium. Columbus, Ohio: Battelle Press, 1981. 164. Snodgrass, D. R., T. L. McLemore, M. V. Marshall, N. F. Wray, E. T. Cantrell, D. L. Busbee, and M. A. Arnott. Induction~of aryl hydrocarbon hydroxylase in buman peripheral blood lympho cytes by chrysene. Cancer Lett. 7:313-318, 1979. - 165. Soos, K. The occurrence of carcinogenic polycyclic hydrocarbons in foodstuffs in Hungary. (In Further Studies in the Assessment of Toxic Actions.) Arch. Toxicol. 4(Suppl.~: 446-448, L980. 166. Sorokin, S. P. The cells of the lungs. In P. Nettlesheim, M. G. Hanna, Jr., and J. W. Deatherage, Jr., Eds. Morphology of Experimental Respiratory Carcinogenesis. AEC Symposium Series 71. Gatlinburg, Tenn.: Atomic Energy Commission, 1970. 167. Spingarn, N. E., and J. H. Weisburger. Formation of mutagens in cooked foods. I. Beef. Cancer Lett. 7:259-264, 1979. 168. Stampfer, M. R., J. C. Bartholomew, H. S. Smith, and J. C. Bartley. Metabolism of benzo~a~pyrene by buman mammary epithelial cells: Toxicity and ONA adduct formation. Proc. Natl. Acad. Sci. USA 78:6251-6255, 1981. 6-73 ~ . .. . .

169. Statham, C. M., C. R. Elcombe, S. P. Szyjka, and J. J. Lech. Effect of polycyclic aromatic hydrocarbons on hepatic micro- somal enzymes and disposition of methylnaphthalene in rainbow trout _ vivo. Xenobiotica 8:65-71, 1978. 170. Stegeman, J. J. Hydrocarbons in shellfish chronically exposed to low levels of fuel oil, pp. 329-347. In F. J. Vernberg and W. B. Vernberg, Eds. Pollution and Physiology of Marine Organisms. New York: Academic Press, 1974. 171. Stegeman, J. J., and J. M. Teal. Accumulation, release and retention of petroleum hydrocarbons by the oyster Crassostrea virginica. Marine Biol. 22:37-44, 1973. 172. Strniste, G. F., and R. J. Brake. Cytotoxicity in human skin fibroblasts induced by photoactivated Polycyclic aromatic hydrocarbons, pp. 109-118. In M. Cooke and A. J. Dennis, Eds. Chemical Analysis and Biological Fate: Polynuclear Aromatic Hydrocarbons. 5th International Symposium on Polyouclear Aromatic Hydrocarbons, Battelle Columbus Laboratories, 1980. Columbus, Ohio: Battelle Press, 1981. 173. Sugimura, 'T., M. Nagao, T. Kawachi, M. Honda, T. Yahagi, Y. Seino, S. Sato, N. Matsukura, T. Matsushima, A. Shirai, M. Sawamura, and H. Matsu~noto. Mutagen-carcinogens in food, with special reference to highly mutagenic pyrolytic products in broiled foods, pp. 1561-1577. In H. H. Hiatt, J. D. Watson, and J. A. Winsten, Eds. Origins of Ruman Cancer, Book C: Human Risk Assessment. Cold Spring Harbor Conferences on Cell Proliferation. Vol. 4. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1977. ~ 174. Thakker, D. R., W. Levin, M. Buening, H. Yagi, R. E. Lehr, A. W. Wood, A. H. Conney, and D. M. Jerina. Species-specific enhancement by 7,8-benzoflavone of hepatic microsomal metabolism of benzo~e~pyrene 9,10-dihydrodiol to bay-region. Cancer Res 41:1389-1396, 1981. 175. Thelestam, M., M. Curvall, and C. R. Enzell. Effect of tobacco smoke compounds on the plasma membrane of cultured human lung fibroblasts. Toxicology 15:203-217, 1980. 176. Thorsteinsson, T. Polycyclic hydrocarbons in commercially and home-smoked food in Iceland. Cancer 23:455-457, 1967. 177. Tilgner, O. J., and H. Daun. Polycyclic aromatic hydrocarbons (polynuclears) in smoked foods. Residue Rev. 27:19-41, 1969. 178. Tomingas, R., F. Pott, and W. l:)ehnen. Polycyclic aromatic hydrocarbons in buman bronchial carcinoma. Cancer Lett. 1: 189-196, 1976. 179. Toussaint, G., and E. A. Walker. Use of high-performance liquid chromatography as a clean-up procedure in analysis of polycyclic aromatic hydrocarbons in alcoholic beverages. J. Chromatog. 171 :448-452, 1979. 180. United Nations, Food and Agriculture Organization, Joint Group of Experts on Scientific Aspects of Marine Pollution (GESAMP). Impact of Oil in the Marine Environment, pp. 91-164. Reports and Studies No. 6. New York: United Nations, 1977 . 6-74 ~. .. . .

181. U. S. Environmental Protection Agency. Mammalian toxicology and human health effects, pp. Cl-C184. In Polynuclear Aromatic Hydrocarbons: Ambient Water Quality Criteria. Report of the Criteria and Standards Division, Office of Water Planning and Standards. Washington, D.C.: Environmental Protection Agency, 1979. 182. U.S. National Cancer Institute. Perinatal Carcinogenesis. Monograph 51. DHEW (NIB) Publ. No. 79-1633. Bethesda, Md.: U.S. Dept. of Health, Education, and Welfare, National Institutes of Health, 1979. 282 pp. 183. Utell, M. J., A. T. Aquilina, W. J. Hall, D. M. Speers, R. G. Douglas, Jr., F. R. Gibb, P. E. Morrow, and R. W. Hyde. Development of airway reactivity to nitrates in subjects with influenza. Amer. Rev. Respir. Dis. 121:233-241, 1980. Vedre, I., M. Rahu, and A. Ilnitski. Benzo~a~pyrene content in waters, soils and potatoes of two regions of Estonia. Eesti. NSV Tead. Akad. Toim. Keem. Geol. 24:237-240, 1975. 185. Vermorken, A. J. M., C. M. A. A. Coos, H. M. J. Roelofs, P. T. Henderson, and H. Bloemendal. Metabolism of benzo [aipyrene in isolated human scalp hair follicles. Toxicology 14:109-116, 1979. 186. Walker J. D., R. R. Colwell, and L. Petrakis. Biodegradation of - petroleum by Chesapeake Bay sediment bacteria. Can. J. Microbial. 92:423-428, 1976. 187. Weaver, N. K., and R. L. Gibson. The U.S. oil shale industry: a health perspective. Amer. Ind. Hyg. Assoc. J. 40:467-466, 1979. 188. Weinstein, D., M. L. Katz, and S. Kazmer. Chromosomal effects of carcinogens and non-carcinogens on WI-38 after short term exposures with and without metabolic activation. Mutat. Res. 46:297-304 ? 1977. 189. Welch, R. M., Y. E. Harrison, A. H. Conney, P. J. Poppers, and M. Finster. Cigarette smoking: Stimulatory effect on metabolism of 3,4-benzpyrene by enzymes in human placenta. Science 160:541-542, 1968. Welch, R. M., Y. E. Harrison, B. W. Gommi, P. J. Poppers, M. Finster, and A. H. Conney. Stimulatory effects of cigarette smoking on the hydroxylation of 3,4-benzpyrene and the N demethylation of 3-methyl-4-monomethylaminoazobenzene by enzymes in human placenta. Clin. Pharmacol. Ther. 10:100-109, L969. White, R. H., J. W. Howard, and C. J. Barnes. Determination of polycyclic aromatic hydrocarbons in liquid smoke flavors. J. Agr . Food Chem. 19 :143-146 , 197 1. 192. Whitlock, J. P., H. L. Cooper, and H. V. Gelboin. Aryl hydro carbon (benzopyrene) hydroxylase is stimulated in human lymphocytes by mitogens and benz~aJanthracene. Science 177:618-619, 1972. 193. Whittle, K. J., J. Murray, P. R. Mackie, R. Hardy, and J. Farmer. Fate of hydrocarbons in fish. Rapp. P. V. Reun. Cons. Int. Explor. Mer 171: 139-142, 1977. 6-75

194. Yamagiwa, K., and K. Ichikawa 195. 196. 197. . Experimental study of the pathogenesis of carcinoma. J. Cancer Res. 3:1-29, 1918. Yang, S. K., H. V. Gelboin, B. F. Trump, H. Autrup, and C. C. Harris. Metabolic activation of benzo~a~pyrene and binding to ONA in cultured human bronchus. Cancer Res. 37:1210-1215, 1977. Yoshida, D., H. Nishigata, and T. Matsumoto. Pyrolytic yields of 2-amino-9H-pyredot2,3-b~indole and 3-amino-1-methyl-5H pyridot4,3-b] indole as mutagens from proteins. Agr. Biol. Chem. 43:1769-1770, 1979. Yoshinaga, T., S. Sassa, and A. Kappas. A comparative heme degradation by NADPH-cytochrome c reductase alone study of _ and by the complete heme oxygenase system: Distinctive aspects of heme degradation by NADPH-cytochrome c reductase. J. Biol. Chem. 257:7794-7802, 1982. 198. Yoshinaga, T., S. Sassa, and A. Kappas. Purification and properties of bovine spleen heme oxygenate. Amino acid composi- tion and sites of action of inhibitors of heme oxidation. J. Biol. Chem. 257:7778-7785, 1982. 199. Yoshinaga, T., S. Sassa, and A. Kappas. The occurrence of molecular interactions among NADPH-cytochrome c reductase, heme oxygenate, and biliverdin reductase in heme degradation. J. Bio1. Chem. 257:7786-7793, 1982. 200. Yoshinaga, T., S. Sassa, and A. Kappas. The oxidative degrada- tion of heme c by the microsomal heme oxygenase system. J. Biol. Chem. 257:7803-7807, 1982. - lung in railroad workers. J.~.M.A. 171:2039-2043, 1959. 201. Zedeck, M. S. Polycyclic aromatic hydrocarbons : A review. J. Environ. Pathol. Toxicol. 3: 537-567, 1980. 6-76

7 SOME FACTORS THAT AFFECT SUSCEPTIBILITY OF HUMANS TO POLYCYCLIC AROMATIC HYDROCARBONS The interaction of chemical pollutants, including the PAHs, and mammalian cells can result in a variety of problems, including toxicity, mutagenesis, carcinogenesis, and teratogenesis. This interaction of chemicals with somatic cells probably results in such end points as cancer, and the interaction of chemicals with germ cells probably results in a variety of hereditary disorders. Many genetic disorders result in a predilection to the development of cancer. The cancer burden in the male population in the United States, although speculative, is distributed approximately as follows: 40% from tobacco-smoking, 10-20% from all diet-related causes, 5t from occupational exposures, it from single-gene inheritance, and 35% from other causes, which may include unknown genetic predisposition and environmental effects.59 The birth-defects burden in the United States is distributed approximately as follows: 5-10% from known teratogens, such as viruses, chemicals, and radiation; 25% from genetic anomalies; and 60-65% from unknown mixtures of genetic predisposi- tion and environmental effects.59 Although monogenic disorders (includ- ing dominants), X-linked recessive disorders, and chromosomal abnor- malities account for only about 5% of the human disease burden, the impact of heterozygous recessively inherited abnormalities similar to the mono- genic disorders is very ill-identified, but could outweigh all other contributions.115 The heterozygous recessively inherited disorders may be the major reason why cancer incidences are not uniformly distributed.95397 In fact, of the millions of people exposed to such environmental chemicals as diethylstilbestrol, estrogen oral contraceptives, vinyl chloride, and cigarette smoke, only a very small proportion develop or express the cancer thought to be associated with these exposures. It is likely that genetic variability within the human population accounts in part for the distribution pattern. As depicted in Figure 7-1, cancer sensitivity can be viewed as a function of inborn susceptibility. Where this inborn or genetic susceptibility is low, cancer expression is low. Where this susceptibility is high (e.g., in single-gene defects), cancer expression is high. The major question is whether the combination of chemical exposure and genetic susceptibility can change significantly the numbers of persons who develop cancer. PAHs are ubiquitous chemicals capable of producing a broad spectrum of biologic responses. Some can cause cancer in a variety of tissues, including lung, liver, kidney, colon, skin, and bladder. In humans, epidemiologic evidence has demonstrated that the incidences of cancers of stomach, nasal cavity and sinuses, lung, and to a lesser extent rectum, testis, skin (e.g., melanoma), brain, liver, pancreas, and hemopoietic 7-1

tissue i.e., leukemia) are correlated with area" captaining high con- centrations of industrial pollutants. 10 ,46' 102,1 2, For many persons, the amount of these agents in the environment may be the rate- deterTnining factor for cancer susceptibility. Thus, the primary need would be to identify and measure the amount o f exposure to the environ- mental pollutants. The advent of a variety of in vitro and in vivo bioassays promises the development of me thods for identi Eying chemicals that are potential carcinogens. In animal-model systems, susceptibility to chemically induced cancers is usually dose-related. However, route, duration, and frequency of administration and such genetic factors as species, sex, and strain all tend to modify the relationship. In humans, mixtures containing PAHs can certainly cause cancer, hut inadequacies in the information on age and trauma but especially on duration, frequency, and intensity of exposure and on the size and characteristics of the exposed population make quantitative estimation of dose-response relationships and the concept of thresholds difficult to interpret. EFFECT OF GENETIC D IFFERENCE The hypothetical stages in carcinogenesis are depicted in Figure 7-2. PAHs probably can show biologic effects at any of these stages. Thus, answers are needed to the following questions: Which stages can PAHs modify in humans? Are there naturally occurring variations in the expression of some of these steps in humans? Can a genetic basis be identified for the regulation of these naturally occurring differences? If so, can the differences result from the action of a single gene system? Can a relationship be shown between the express ion in the gene locus and PAH-mediated effects? PAH-induced effects in humans could depend on exposure, uptake, and distribution of the chemicals; their metabolic activation and inactiva- tion; DNA-repair capacity; "promoters"; and the extent of immunocompe- tence. Each of these is discussed below. UPTAKE AND DISTRIBUTION OF PAHs IN TISSUES The distribution of PAHs in tissues or cells depends on the route of exposure. According to the results of Rees et al.,1 the distribution of benzota~pyrene (BaP) in tissue other than at the site of absorption (i.e., intestine) depends on two phases: accumulation of the BaP on the tissue and passive diffusion through the tissue. These two phases underlie these authors' views about the apparent exponential nature of the accumulation of BaP as a function of dose. The exponential increase could be very important, but it must be pointed out that humans are rarely exposed to BaP at concentrations greater than 200 AM (i.e., 50 legal) under "normal" circumstances. Concentrations of a variety of PAHs (e.g., pyrene, anthracene, and BaP) in human tissues average about 1,100 parts per trillion (ppt) in fat tissue and 380 ppt in liver.ll9 BaP can vary 7-2

from 0.3 No 15,000 parts per billion (ppb) in bronchial-carcinoma tissue.18 Most of the subjects in the study of Tomingas et al.184 were cigarette-smokers, but no obvious correlation between BaP concentration and extent of smoking was seen. The PAHs observed in addition to BaP included fluoranthene, benzotbifluoranthene, and perylene. Reasons for differences in tissue distribution are not known, but, inasmuch as most of these chemicals are inducers and substrates for microsomal enzymes, tissue variation in cytosol and nuclear receptors could be important. In rodents, the induction of the microsomal mono- oxygenase system by some PAHs depends on the presence of particular cytosol receptor proteins.56314231 3 These receptor proteins are not evenly distributed in all tissues, but are highest in thymus and lung, lower in liver and kidney, lower yet in testes, brain, and skeletal muscle, and not detectable in pancreas, adrenal, or prostate.l5 Most importantly, receptor proteins are found in high concentrations in strains of animals or cultured cells in which PAHs induce the enzyme aryl hydrocarbon hydroxylase (AHH) and are nondetectable in those in which AHH is nonrespons ive . 56 , 142 This correlation also extends to humans, in whom the concentration of a BaP-binding plasma component is correlated with the capacity of lymphocytes to be induced for AHH activity in culture.104 A cytoplasmic receptor for BaP, which did not cross-react with 7,12-dimethy31benz~ajanthracene, has also been reported for human cells in culture. 1 The presence of some of these receptors is under specific genetic control in animal models,l22~143, so uptake and distribution, at least in particular persons, could be under a form of genetic control. METABOLISM PAHs are metabolized in a variety of ways, with the microsomal mono- oxygenases (e.g., AHH) probably most important. Steady-state activities of these enzymes vary Animals and are linked to susceptibility to some PAH-mediated cancers.7 ~ 1 In humans, the data are much less clear. Table 7-1 summarizes the studies that suggest a correlation between high AHH inducibility (and usually high induced-AHH activity) and cancer susceptibility, and Table 7-2 summarizes the studies that suggest the converse. Reasons for the contradictory results probably lie in methodologic variations, such as the use of different cell types, different assays, and different assay conditions. The most easily accessible and therefore commonly used Lyman tissue is She peripheral blood lymphocytes. Nutri- tional state,1 drug intake,8 age,35 and disease state74 influence the capacity of the lymphocytes to respond to mitogen. These influences have not been assessed in determining their relationship to the AHH activity observed in cultured lymphocytes. Variations in AHH activ- ity in lymphocytes have been observed to occur seasonally in some geo- hi 1 ations 128$129,154 but whether they result from in vivo or in vitro factors is not known. 7-3 ~ . it. . ..

A variety of in vitro conditions are known to influence AHH activity. The initial concentration of lymphocytes affects the time course and amount of control and induced AHH activity.7 The type and lot of serum Supplement infuence the control and induced AHH activity.5 ,7 In fact, some lots of feta)-galf serum are capable of causing mitogen activation of lymphocytes. O The numbers of cultured T cells may affect the AHH activity observed.67 In studies using cultured human tissue, two important aspects are the question of the variable degree of AHH activity in different cell types202 and the question of large variations between and within individuals in both AHH activity and microsome-mediated BaP-DNA adduct formation. ' 3 Blood monocytes and pulmonary alveolar macrophages are examples of other human cell types whose AHH activity is Correlated with that in lymphocytes or cultured human tissue, but there are problems of accessibility with each of these cell types. If the cell samples are cultured and assayed on the same days, the v5r~2t~30 seems to be ac3eptable.5°379 Culturing lympho- cytes ~ ~ or monocytesl2 from fraternal or identical twins at the same time has shown that AHH activity is under a degree of genetic control, and the numbers of genes in question are probably small. Thus, the genetic component most likely results in a unimodal frequency distribution that is skewed in the populations of individuals toward those with higher AHH activity,7831ll rather than the trimodal distribution originally reported.72 To circumvent many of the in vitro problems, the use of cryopre- served tissue may be an alternative, in that lymphocytes can be cryo- preserved before mitogen activation and still have ted capacity to be mitogen-activated and then assayed for AHH activity. The relative AHH activities among the lymphocyte samples from different individuals are similar, whether the assays are conducted on freshly cultured lymphocytes or after cryopreservation.82 Cryopreservation allows the culture and assay at the same time of cells from different organisms collected in diverse geographic locations and over extended periods. The use of cryopreserved lymphocytes 3 control of some basic culture variables--such as initial lymphocyte concentration (1.0 x 106 cells/ml) and lot and type of serum supplement (e.g., human AB serum)--and assaying AHH activity at two times to ensure detection of peak activity can yield the data presented in Figure 7-3. Data were taken on a group of 51 per- sons who were on hospital diets for at least 2 d before phlebotomy, who were not on any medication, and who were eventually followed for complete clinical diagnosis. Viability of cells was measured by assay for the NADH-dependent cytochrome by reductase (using cytochrome c as a sub- strate) activity (Cyt c). Carcinogen-metabo~i~gg activity is presented in terms of units of AHH per unit of Cyt c.7 ~ The degree of mitogen activation was also measured. Data analyses showed that: ~ Cryopreserved lymphocytes from over 957 of the normal and cancer patients were mitogen-activated. 7-4

· Lymphocytes from lung-cancer patients were mitogen-activated as efficiently as lymphocytes from noncancer patients (actually better; = 0.001). O The 14 highest AHH activities were found in patients with lung cancer, with the mean in the 21 lung-cancer patients (0.89 unit AHH/unit Cyt _) being significantly higher than that in the 30 non-lung-cancer patients (0.47 unit AHH/unit Cyt c). The higher AHH activities were not directly related to higher degrees of blastogenesis and were not related to cigarette-smoking history, tumor type, tumor location, or family history of cancer. Whether high AHH activity is the cause or the result of lung cancer cannot yet be answered. In animal-model systems, some PAHs cause tumors of the lymphoreticu- lar system, and a genetic association for this activity at the Ah locus has been suggested.29~1l3 Although this is only presumptive, there may be a similar relationship in human leukemia patients who were recently shown to express lower AHH activity (as in animal-model systems);ll in other studies, the first-degree relatives of leukemia patients expressed normal AHH activity.90 The results of these studies are interesting and certainly need to be confirmed and extended. The extended studies should be multifaceted; that is, they should simultaneously measure more than one enzymatic end point. Perhaps an appropriate group of assays would include an assay for AHH, as described in the literature; an assay for all B3aP ~§abolites via HPLC; an assay for particulate P-450s via immunoassays;1 1, and an assay for mRNA expression of the P-450 genes with cloned UNA fragments containing the P-450 genes.116 Human tissues should be used where possible. There is probably a degree of genetic control of AHH activity in the human population, and this enzyme may play a role in determining susceptibility to PAH-mediated cancer and other diseases. DNA BINDING, DAMAGE, AND REPAIR Many PAHs are converted by the microsomal monooxygenases to forms that bind covalently to a variety of cellular macromolecules, including nucleic acids (see Chapter 5 and Phillips and Simsl40~. Evidence of the importance of DNA binding is exemplified by the observation that varia- tions in DNA-repair capacity seem to play a major role in determining the toxic, mutagenic, and3 t :00s f49ming ac t ivit ie s o f many chemical care i 0 In animal-model systems, the amount of PAH metabolism is determined by the activity of the microsomal monooxygenases, and variations in these enzymes result in concomitant changes in the binding of chemicals to DNA.112 In cultured human tissue, hydrocarbon-DNA binding also occurs as the result of microsomal monooxygenase-mediated metabolism,6~55 and variations in metabolic activity are asso5:iated with concomitant varia- tions in binding of hydrocarbons to DNA. The major DNA adduct often results from the interaction of specific metabolites of PAHs (diol- epoxides) and the N7 of deoxyguanosine.l24,l35 Other products a 7-5 ~; ~` ..

found, including interactions with the N4 deoxyadenosine,177 the back- bone phospt~tl,70f ONA, 1 and the exocyclic amino group of deoxy- adenosine. ~ The latter may be important, because its formation from various PAH-like chemicals closely parallels their carcinogenic potencies on mouse skin.27 No apprec~,b{~ syggificity of binding with respect to base sequence is apparent, ~ 8, but binding may be influenced by chromatic structure, with a greater extent of binding associated wi th internuc leosomal regions.6 ,76 ' A potentially important anomaly is that, although in vitro metabolism of BaP to forms that bind to DNA parallels the AHH activity of the micro- somal preparations and the Genetic background of mice used to generate these microsomal samples,13 the in viva results from strains of mice that differ widely in ASH activity so that there is very little strain variation in BaP-DNA binding. ~ Probably more crucial to carcinogenicity is the geometry of the binding in relation to later excision repair by endonucleases.48 The binding of different residues and different chemical groups within residues dramatically affects excisibility. These chemical-DNA adducts are either repaired, not repaired, or misrepaired (see Figures 7-2 and 7-4). The fate of these adducts determines whether a cell remains normal, mutates, or dies. Repair capacity can be separated into two major types--excision repair and postreplication repair.l49 Excision repair is the in situ removal and replacement of chemically modified ONA so that the original DNA sequence is re-established. For a variety of reasons, excision- repair systems usually do not remove all the modified bases; so the ONA very often replicates, even though some unexcised damage may be present. This replicated UNA usually has gaps in the newly synthesized strand opposite the DNA adduct. The gaps are fillip in by postreplication repair--also termed "recombination repair." O Figure 7-3 depicts how these two processes of repair contribute to the cells' survival of the damaging effects of chemicals like PAHs. A combination of both methods is involved in the repair of hydrocarbon-bound DNA.1OO A large number of both constitutive and inducible enzymes are involved in this ONA-repair process.47 The exact role of these enzymes is not known, but it seems that rather small changes in any of the enzyme activities can have great effects on the repair process and eventual bio- logic expression of the DNA adducts. Moreover, it has been recently shown in prokaryotes that the DNA adduct itself is not likely to be mutagenic, but rather that the mutagenic event is induced by the action of the DNA-repair enzymes themselves.] Natural variations in DNA-repair capacity occur in humans. These variations are exemplified by the existence of genetic diseases that are associated with defects in DNA repair. Table 7-3 presents a list of such diseases, their modes of inheritance, the specific tumors associated with them, and their proposed DNA-repair defect. These genetic diseases are 7-6 Am .. .. ..

associated with a high incidence of malignancy, compared with the incidence in the general population, and often a specific malignancy is involved (see Table 7-3~. The incidences for persons who are genetically homozygous for xeroderma pigmentosum, ataxia telangiectasia, and Fanconi's anemia are about 10-5, and for those who are heterozygous, about 10-2. Those who are heterozygous for ataxia telangiectasia and are less than 45 yr old have a fivefold increase in the risk of cancer,180 and those heterozygous for Fanconi's anemia may account for 5% of all leukemia deaths (approximately a fivefold increase in susceptibility).179 Because these people are deficient in the ability to repair radiation- induced DNA damage and chemical-induced DNA damage, 169 it has been suggested that alteration in DNA-re~air capacity may put them at greater risk of chemically induced cancers. 68 It must be pointed out that many of these diseases, especially ataxia telangiectasia, are also associated with abnormalities of the immune system. Thus, genetic disease may result in higher risks of cancer via deficiencies in DNA-repair capacity or immunocompetence. Among the normal population of humans, there are probably subtle variations in DNA-repair capacity, but whether these variations are genetically controlled or are related to cancer risk remains to be determined. PROMOTION AND COCARCINOGENESIS Many s tudies have shown that a number of modifying fac tars can increase the effect of low-dose or low-potency carcinogens that by themselves would be insufficient to induce malignancies.l09~200 Many PAHs are complete carcinogens; that is, they have both initiating and promoting activities. Others--such as pyrene, benzote~pyrene, fluoranthene, and benzotghi~perylene--are weak complete carcinogens and weak cocarcinogens.l9l'192 It is difficult to determine what role PAHs might have in tumor promotion in humans, because there are no good methods for measuring this activity in the human population. Such end points as induction of ornithine decarboxylase activity,13 phosDholipid synthesis,l59~178 inflammation,~73 protease activit ,~87 cellular proliferation,57 decrease in differentiated states,;6~201 and formation of "dark cells''l48~172 are manifestations of man romoters, and many PAHs can induce at least some of these changes.l95~500 But no single end point correlates with the promoting activity of all the different chemicals that have promoting activity. In animal systems, there seems to be a genetic basis for promota- bility, in that different strains of mice express different suscepti- bility to promotion during the standard two-stage carcinogenesis assay. Such strains as CD-1 and BALB/c are relatively resistant, whereas the specifically derived SENCAR strain (i.e., sensitive to carcinogenesis) is very sensitive to promotion of skin cancer~78~58 The molecular basis of this difference has not been defined, but recent informal ion suggests that the skin itself has the sensitivity, inasmuch as skin from SENCAR mice remains sensitive to promotion even after grafting to BALB/c mice.203 7-7

No genetic variation in promotability in humans has been described. However, the fact that pyrenes may have promoting and cocarcinogenic activity, the possibility that such activity plays a major role in cancer formation in humans, and the absence of effective end points in the human population all suggest that much more work is necessary before the role of PAHs in promotion can be understood. I~4UNOCOMPETENCE _ Substantial interest has centered on the role of the immmune system in preventing the expression of malignancy by recognition and destruc- tion of newly formed malignant cells. The concept of "immunosurveil- lance," however, has not been well supported, and, in fact, "stimula- tion" of malignant cells may even occur.75 Immunodeficient persons do have a greatly increased risk of develop- ing a malignancy of the lymphoreticular system.17~60~93~126 The exact mechanism responsible for the increase, however, is not clear. A number of genetic disorders in humans are associated with immuno- deficiencies. These disorders include ataxia telangiectasia, Wiskott- Aldrich syndrome, Bloom's syndrome, common variable immunodeficiency, selective IgA deficiency, Bruton's agammaglobulinemia, severe combined immunodeficiency, selective IgM deficiency, and immunodeficiency with normal or increased immunoglobulins.73 These immunodeficient genetic disorders are usually heterogeneously linked with a variety of other distinct underlying defects. For example, persons with ataxia telangiectasia and Bloom's syndrome have severely impaired DNA-repair capacities,169~195 and those with severe combined immunodeficiency also have adenosine deaminase deficiency.73 Therefore, it is difficult to determine the reasons for the increased cancer susceptibility of these persons. Epidemiologic evidence fails to support the idea that immunosurveillance mechanisms are generally involved in carcinogenesis 5 but does provide clues to immunologic processes that may predispose to particular neoplasms.38 In animal-model systems, PAHs can cause tumors of the lympho- reticular system, and association with the Ah locus has been suggested.29~113 In humans, exposure to some hydrocarbons, such as benzene, has been repeatedly associated with leukemia. Whether variations @ ~ Ln 1mmunocompetence occur naturally in the normal population and whether PAHs, as a group of environmental contaminants, pose a special risk to persons with such variations are not known. STAGE OF DEVELOPMENT . Some cell types undergo periods of heightened sensitivity to chemicals during their normal growth cycles. For example, in animal- model systems there are striking differences between geru-cell stages in

the chemical induction of dominant lethals, translocations, and specific- locus mutations. l4, 160 Moreover, the fetus is at greater risk than the mother, owing to high doses of environmental chemicals; the permeability of the blood-brain barrier is greater, and liver-enzyme conjugating function is poorer.61 The greater the lipid solubility of a chemical, the greater its placental transfer; and the placenta is readily permeable to chemicals with molecular weights less than 600. Most PAHs fit into these categories, and in animal-model systems such PAHs as BaP, 3-methylcholanthrene, and 7,12-dimethylbenz~aJanthracene cause oocyte and follicle destruction and embryo lethality and resorption and have a greater incidence of malformation and even cancer in surviving embryos.88~103~171~190 In humans, gross congenital abnormalities occur in some 2t of all infants and are the cause of about 15t of the deaths of infants less than a year old. Exposure to such agents as viruses, mercury, DUT, CO, and polybrominated biphenyls probably accounts for 5-10t of the birth defects; genetic abnormalities cause 25%; and the causes of the remainder are largely unknown.61 Interactions in the intrauterine environment between genetic predisposition and chemical and biologic factors are probably responsible for these birth defects. Although occupational exposure of human males52 and both paren-ts204 to PAHs was not associated with increased cancer incidences in the offspring, recent work has suggested that a combination of chemical exposures of both parents (especially the mother) resulted in higher incidences of brain tumors in the offspring. 137 Maternal cigarette-smoking is associated with decreased birthweight, increased perinatal morbidity and mortality, and other harmful effects on the newborn.l41 The PAHs in cigarette smoke may account for some of its biologic activity, inasmuch as a relationship has been shown between cigarette-smoking, induction of AHH activity in human placental tissue,ll4'l98 and a decrease in placental size;135 PAHs are the major class of AHH inducers found in cigarette smoke, 83 and thus it is important to note that BaP, which is in cigarette smoke, can cross the placental barrier.92 Because PAHs must be metabolized before they produce a biologic effect, the impact of PAHs on maternal and fetal tissues can be quite complex. Some examples of these complexities are differences in developmental patterns of specific enzymes, the relative importance of maternal and fetal metabolism, the role of metabolism in placental tissue, the relative importance of hepatic and extrahepatic metabolism, and sex differences in developmental patterns. The induced and control forms of AHH and acetanilide 4-hydroxylase are temporally regulated both before and after the birth of animals.68 The deactivation of conjugating enzymes (e.g., UBP-glucuronyltransferase, sulfotrans- ferase, and N-acetyltransferase) is also temporally regulated both before and after birth, but this regulation can be quite different from that of AHH.94 The relation between activation and inactivation can be influenced by the sex of animals.70 Shum et al.171 showed that both the fetal and maternal enzymes play an active role in determining the ultimate fetal toxicity of BaP. Using specific crosses between AHH-responsive and AHH-nonresponsive strains, these authors could show 7-9

that when the mother was nonresponsive the enzyme capacity of the fetal tissue determined the toxicity of BaP, but that when the mother was AHH-responsive there was no difference in fetal toxicity between nonresponsive and responsive fetuses. Mice seem to have AHH activity as early as about 7.5-8.5 d of gestation.40 This activity slightly increases before birth, but increases greatly in the first few days after birth94 and then slowly decreases as the mouse ages.68 It should be pointed out that in vivo exposure to BaP, in addition to inducing higher AHH activity in mouse fetal tissue, can suppress bumoral immunity in animals that survive and can cause about a 10-fold increase in the incidence of various tumors in surviving animals.l90 It seems likely that, in rodents (and perhaps in bumans), PAHs can be taken up and distributed through the placenta intact or in the form of metabolites, that the metabolites themselves can cause fetal toxicity or the delayed effects of immune suppression or cancer, and that intact PAHs can cause fetal enzyme induction, metabolism, and the sequelae mentioned earlier. MODIFYING FACTORS - A variety of environmental factors can mitigate or exacerbate the inherent sensitivity of mammalian tissues to PAHs. These factors are probably at least as important as some of the genetically controlled differences discussed earlier and tend to make genetic differences less distinct. Two factors known to modify PAH carcinogenesis, at least in animal-model systems, are the physical state of the PAH and the nutritional state of the exposed organism. PHYSICAL STATE OF PAH . The sources and the formation of PAHs in the environment are dis- cussed in Chapters 1-3. Most of them are found as mixtures and many are found in association with particles, such as cigarette-smoke particles, i74 fossil-fuel combustion products, 9 coal flyash, 77 and asbestos fibers.86~105 This association can be important, because PAHs in the presence of or adsorbed on particles are transported through membranes more e f f ic iently,75 are cleared from tissue more slowly, 25 and have a different tissue distribution--that determined by the particle size, rather than by the size of the free PAH.147 The increased uptake results in more efficient induction of AHH activity at low PAH concentrations.l°5 Those exposed to particles containing PAHs are probably at greater risk of various cancers.166 Uptake, distribution, and metabolism of PAHs can be so altered by particles that those who normally would be unaffected by the PAHs may be adversely affected. NUTRITIONAL STATE OF HOST Nutritional status can substantially modify the toxicity of some environmental pollutants. For example, specific dietary 7-10 ~... . .

Next: 7 SOME FACTORS THAT AFFECT SUSCEPTIBILITY OF HUMANS TO POLYCYCLIC AROMATIC HYDROCARBONS »
Polycyclic Aromatic Hydrocarbons: Evaluation of Sources and Effects Get This Book
×
Buy Paperback | $125.00
MyNAP members save 10% online.
Login or Register to save!
  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!