Drinking Water and Health, Volume 1 (1977) / Chapter Skim
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II CHEMICAL CONTAMINANTS: SAFETY AND RISK ASSESSMENT
II CHEMICAL CONTAMINANTS: SAFETY AND RISK ASSESSMENT
Pages 19-62
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From page 19... ...
. Toxicity data obtained from laboratory animals will generally have to be relied on for estimating human risk, if we are to control human exposure to carcinogens.
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From page 20... ...
The major toxicological and epidemiological efforts should therefore be directed to characterizing and identifying pollutants whose biological effects include chronic, irreversible, and progressive diseases, such as cancer. It is necessary to develop risk estimates for large human populations of varied susceptibilities that are exposed to small concentrations of such toxic pollutants, including carcinogens.
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From page 21... ...
Drinking water contains low concentrations of many chemicals, some of which, if ingested for a long time, could have delayed toxic effects. The insidious eject of chronic exposure to low doses of toxic agents is difficult to recognize, because often there are few early warning signs and, when signs are ultimately observed, the effects may have become irreversible.
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From page 22... ...
is lacking 4 yr from the time a mutagenicity study is completed, nonthreshold methods be used to establish risk.] Chronic exposures and chronic effects are different (Casarett, 1975~.
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From page 23... ...
Prediction of adverse effects from short-term studies is possible if the critical dose and the rate-limiting factors that determine reversibility are known. Without this knowledge, evaluation of toxicity will generally deal more with the possibility of irreversible effects than with speculatively reversible elects.
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From page 24... ...
This might constitute an initial approach to the development of rational risk estimates for toxic effects other than cancer. Clearly, a major research effort is needed.
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From page 25... ...
From another point of view, Well (1972) , considering statistics and judgment in safety evaluation, wrote: "No matter what the biological erect, at some concentrations under some sets of conditions, a dose level must exist below which no biological damage will occur during the life-span of the great majority of men.
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From page 26... ...
1. Genetically self-propagating ejects, e.g., somatic or germ-cell mutation that culminates in a malignant neoplasm or is transmitted to later generations: Assume no threshold, assume a linear dose-response at low doses, and estimate risk.
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From page 27... ...
of the long-term effects of potentially toxic agents, and how can these results be used to estimate possible risk to the human population? " Summary of Principles for Extrapolating Animal Toxicity To Humans Despite wide gaps in our knowledge of the metabolism and ultimate fate of chemicals in man, properly conducted experiments will yield results that can improve our estimates of the risk to human populations from long-term exposures.
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From page 28... ...
Studies in laboratory animals must be used to predict the safety of environmental chemicals. Human epidemiological studies cannot be used to predict nor assure safety, for several reasons: 1.
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From page 29... ...
The General Problem Of Extrapolation The knowledge and insight that provide a basis for more successful extrapolation are rapidly increasing. The value of tests on laboratory animals is most easily estimated when the chemical agents tested are ultimately administered to, or confront man in a manner similar to the animal exposure, as in the drug-development process.
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From page 30... ...
Specific Problems In Extrapolation Experiments on laboratory animals are generally performed under highly standardized conditions, with controlled diet, temperature, humidity, and light-dark cycles, and usually with genetically homogeneous animals, such as inbred mice, rats, or beagles. Thus, one obtains reasonably precise and reproducible information on the toxicity of a substance under
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From page 31... ...
Therefore, environmental and genetic variability must be considered in the process of extrapolation. Man is generally exposed to toxic pollutants in the water supply through his gastrointestinal tract, and laboratory animals should be exposed in the same way.
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From page 32... ...
Typically, about 102-103 experimental animals are tested, whereas the population of humans to be protected may be 108-109. The human population is genetically heterogeneous, whereas test populations of animals, as a rule, are relatively inbred.
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From page 33... ...
For example, reduction of nitrate to nitrite permits the formation of highly carcinogenic nitrosamines by reaction with secondary amines from the diet. The bacterial populations in the gastrointestinal tract vary between species and within species, and in the same individual from time to time.
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From page 34... ...
Design Of Laboratory Experiments On Animals In designing assay procedures, the route and type of human exposure should be duplicated as closely as possible. Because it is often impossible, a priori, to determine specific susceptibility-and because man may often be the most susceptible species more than one species of laboratory animal should be used.
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From page 35... ...
Some logical and statistical considerations in the design and conduct of the animal experiments affect the extrapolation. Two major considerations are the structure of the experiments how many doses, how spaced, inbred vs.
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From page 36... ...
In this case, peak pentobarbital concentration in plasma is diminished by about 50%, and the duration of the elective plasma concentration is doubled (Bush et al., 1966~. Another difficulty in extrapolating from laboratory animals to man is the dose-duration problem.
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From page 37... ...
If an eject can be caused by a single hit, a single molecule, or a single unit of exposure, then the eject in question cannot have a threshold in the dose-response relationship, no matter how unlikely it is that the single hit or event will produce the effect. Mutations in prokaryotic and euka~yotic cells can be caused by a single cluster of ion pairs produced by a beam of ionizing radiation.
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From page 38... ...
If such thresholds exist, they occur at sufficiently low doses that it would require massive, expensive, and impracticable experiments to establish them. In view of the common finding-for example of a linear doseresponse relationship (unaffected by dose-rate)
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From page 39... ...
Because many carcinogenic agents act like radiation in producing mutations, chromosome aberrations, and cell killing, we see this as an additional argument against the likelihood of thresholds in the dose-response curves of these agents. HETEROGENEITY OF THE POPULATION The human population in the United States- the population we are trying to protect is a large, diverse, and genetically heterogeneous group exposed to a variety of toxic agents.
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From page 40... ...
With this modification, the model became consistent with both human and animal data that showed tumor incidence as related to either dose or the square of dose, but not higher powers. It should be noted that the theories of Nordling, Stocks, and Armitage and Doll are based on the concept that carcinogenesis has a single-cell origin, whereas a theory proposed by Fisher and Holloman (1951)
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From page 41... ...
They made two basic assumptions: that the cancer process is single-cell in origin, possibly with multiple steps between initiation and complete alteration, and that the growth period of the completely altered cell is basically independent of the degree of exposure. For direct carcinogenic processes, in which the agent or its metabolite acts at the cellular level to produce an irreversible change, they concluded that most models of carcinogenesis will be linear for low doses.
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From page 42... ...
Experimental or observational evidence of the existence of an "actual" threshold is usually presented in the form of a dose-response graph, in which the percentage of animals with tumors or the average number of tumors per animal is plotted against the dose of the carcinogen. Either the existence of doses that do not lead to an increase in tumor incidence over controls, or the extrapolation of such curves to low doses that apparently would result in no tumor increase, is cited as an indication of the existence of a threshold below which no response is possible.
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From page 43... ...
It is much more likely that, if thresholds do exist, not all members of the population have the same one. The human population is a very diverse, genetically heterogeneous group that is exposed in different degrees to a large variety of toxic agents.
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From page 44... ...
(1961) to induce an increased convexity in dose-response curves at low doses.
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From page 45... ...
represents the dose-induced response rate at a dose level d and A is the threshold below which no response can occur. If we assume that the population consists of individuals with different thresholds, and that these thresholds vary according to some probability distribution F(~)
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From page 46... ...
In addition, when considering the possibility of carcinogenic thresholds, one should keep in mind that no agent has been found to induce a type of cancer that has not been previously described. It is possible, perhaps even likely, that many carcinogenic agents act by the same mechanism on the same target cells.
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From page 47... ...
Therefore, to estimate the probability of response at dose levels outside the experimental range, it is necessary to make an assumption concerning the form of the dose-response relationship at low doses. As noted above, many quantitative theories of carcinogenesis have been proposed that relate the occurrence of detectable tumors to both the quantity and the duration of exposure to the carcinogenic agent.
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From page 48... ...
. Therefore, in extrapolating from high dose levels to low doses, the risk attributable to the carcinogen, after correcting for background, will depend on the magnitude of the coefficient, A'.
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From page 49... ...
Therefore, one must have some information concerning doses at which the tumor incidence is in the lower convex portion of the dose-response curve. Although low-dose extrapolations are out of the question for highincidence data, one can calculate some relative dose information that can be used in expressing concerns over possible adverse health ejects.
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From page 50... ...
. Animal experimentation (Berenblum, 1947)
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From page 51... ...
. since there are many carcinogenic agents in our .
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From page 52... ...
The insidious ejects of chronic exposure to low doses of toxic agents is difficult to recognize, because there are few, if any, early warning signs and, when signs are ultimately observed, they often imply irreversible ejects. For example, cancer induction in experimental animals, even with the most potent carcinogenic chemicals, requires at least several months and in many instances a whole lifetime.
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From page 53... ...
Evidence that circumstances leading to cancer induction in humans are also applicable to experimental animals stems from the very first observation of chemical carcinogenesis the appearance of cancer of the
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From page 54... ...
Yamagiwa and K Ichikawa, found in l91S that extracts from coal tar cause cancer when applied to the skin of experimental animals.
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From page 55... ...
Principle 3 THE EXPOSURE OF EXPERIMENTAL ANIMALS TO TOXIC AGENTS IN HIGH DOSES IS A NECESSARY AND VALID METHOD OF DISCOVERING POSSIBLE CARCINOGENIC HAZARDS IN MAN The most commonly expressed objection to regulatory decisions based on carcinogenesis observed in animal experiments is that the high dosages to which animals are exposed have no relevance in assessment of human risks. It is therefore important to clarify this crucial issue.
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From page 56... ...
This means that chronic-toxicity studies, which are imperfect assay systems for carcinogenicity testing, should not be used as the sole criterion in the assessment of risk. Principle 4 MATERIAL SHOULD BE ASSESSED IN TERMS OF HUMAN RISK, RATHER THAN AS SAFE OR UNSAFE The limitations of the current experimental techniques do not allow us to establish safe doses, but with the help of statistical methods we may be able to estimate an upper limit of the risk to human populations.
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From page 57... ...
Finally, mankind is already exposed to many carcinogens whose presence in the environment cannot be easily controlled. In view of the nature of cancer, the long latent period of its development, and the irreversibility of chemical carcinogenesis, it would be highly improper to expose the general population to an increased risk if the benefits were small, questionable, or restricted to limited segments of the population.
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From page 58... ...
Research on statistical methods and mathematical models for estimating low dose ejects should be encouraged. Statistical work is pratically nonexistent for effects other than carcinogenesis.
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From page 59... ...
4. Research on statistical methods and analytical models for describ ing and estimating the ejects of long exposure to low doses of toxic substances.
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From page 60... ...
Presented at the NIEHS Conference on the Problems of Extrapolating the Results of Laboratory Animal Data to Man and of Extrapolating the Results from High Dose Level Experiments to Low Dose Level Exposures, Pinehurst, N C., March 10-12.
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From page 61... ...
Presented at the NIEHS Conference on the Problems of Extrapolating the Results of Laboratory Animal Data to Man and of Extrapolating the Results from High Dose Level Experiments to Low Dose Level Exposures, Pinehurst, N.C., March 1~12. Wedderburn, N
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From page 62... ...
62 DRINKING HER MID H"~H ail, C.S.
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