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8 ESTIMATING THE RISKS
Pages 323-372

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From page 323...
... Thus, their ingestion of pesticide residues on these foods may be proportionately higher than that of adults. For certain chronic toxic effects such as cancer, exposures occurring early in life may pose greater risks than those occurring later in life.
From page 324...
... Information on health risks may be obtained directly from epidemiological and other studies of humans or indirectly through toxicological experiments conducted in animal models. Although results of laboratory studies are applicable to humans only indirectly, they can be used to predict potential health hazards in advance of actual human exposure and thus continue to be used widely to identify substances with potential toxicity.
From page 325...
... And third, the committee proposed an additional 10-fold safety factor in the absence of adequate toxicity data, for an overall safety factor of 100. The use of these factors was later supported in a report by the Safe Drinking Water Committee in a reexamination of the earlier risk assessment practices (NRC, 1986~.
From page 326...
... The EPA has recommended using the term uncertaintyfactor (UF) rather than safety factor in recognition of the fact that the ADI does not guarantee absolute safety consistent with more recent recommendations of the Safe Drinking Water Committee (NRC, 1986~.
From page 327...
... is selected for calculation of the reference dose, five factors may contribute to the composite uncertainty factor: · the need to extrapolate from animal data to humans when human exposure data are unavailable or inadequate; · the need to accommodate human response variability to include sensi tive subgroups; · the nature, severity, and chronicity of the effect; · the need to accommodate the necessity of using LOAEL rather than NOAEL data; and · the need to extrapolate from a data base that is inadequate or incomplete. The overall UF may vary from 1 to 10,000, depending on the combination of these individual factors, but usually does not exceed 100.
From page 328...
... The EPA now uses the linearized multistage model for low-dose cancer risk estimation. The most important aspect of this practice is not the choice of the multistage model itself for risk estimation purposes but, rather, the linearized form of the model.
From page 329...
... This is expressed as follows in the current Guidelines: If a carcinogenic agent acts by accelerating the same carcinogenic process that leads to the background occurrence of cancer, the added effect of the carcinogenic process at low doses is expected to be virtually linear.
From page 330...
... Nonlinearity at High Doses Linearity at low doses does not imply that the dose-response curve will also be linear at high doses. In particular, curvature at high doses can result from factors such as saturation of absorption or elimination pathways or the alteration of pharmacokinetic processes involved in metabolic activation (Hoer et al., 1983~.
From page 331...
... The dose-response curve for tumor induction can be linear or nonlinear for a genotoxic agent that acts completely independently of background. If neoplastic conversion can result from a single mutagenic DNA lesion, the linearity of adduct formation at low doses implies linearity with respect to tumor induction (Lutz et al., 1990~.
From page 332...
... Biologically Based Cancer Models. The multistage model has a long history of use in theoretical descriptions of carcinogenesis (Whittemore and Keller, 1978; Brown and Koziol, 1983; Armitage, 19851.
From page 333...
... The biological basis for the multistage model is incomplete in that it does not incorporate tissue growth or cell kinetics. Furthermore, as many as six stages may be required to describe dose-response curves with high upward curvatures, raising questions of biological interpretation.
From page 334...
... or logistic model to describe the dose-response relationship for promotion, these investigators developed estimates of risk that were appreciably lower than those based on the linearized multistage model. Before this model can be recommended for routine application, however, its statistical properties require further study, especially with respect to predictions of risk at low doses (Portier, 1987~.
From page 335...
... uses the linearized multistage model to estimate risk at low doses. A risk assessment analysis based on the LMS uses qua (a quantitative carcinogenic potency factor)
From page 336...
... , the toxicity data base used in either the time-independent or time-dependent models for cancer risk assessment derives from carcinogenicity studies in young adult or adult laboratory animals whose responses may not be representative of those in neonates and weanlings. Newborn animals are often found to be more sensitive to certain carcinogens than are older animals (Rice, 1979~.
From page 337...
... The activity of drugs in human infants and newborns has also been related to body surface area (Wagner, 1971; Homan, 1972~. On the basis of an empirical study of the carcinogenic potency of chemotherapeutic agents, Travis and White (1988)
From page 338...
... In 1991, the EPA proposed using this approach in its recent guidelines for developmental toxicity risk assessment (EPA, 1991~. A benchmark dose is defined as the lower confidence limit for the dose corresponding to a specific increase in the response rate over the background rate.
From page 339...
... The application of PBPK models requires extensive information on the anatomy and physiology of the test animals, the solubility of the test chemical in various organs and tissues, and biochemical parameters governing metabolism (Andersen et al., 1987~. If metabolic activation can be adequately characterized in terms of a suitable pharmacokinetic model, the dose delivered to the target tissue may be used in place of the administered dose for purposes of doseresponse modeling.
From page 340...
... Fetal exposure to trichloroethylene was estimated to range from 67 to 76% of the maternal exposure; fetal exposure to the trichloroacetic acid metabolite was 63 to 64% of that of the dam. The model fitted data obtained after exposure by inhalation, oral Savage, or via drinking water.
From page 341...
... The exposure of the pups to trichloroethylene from maternal milk was small, representing only about 2% of the exposure of the dam. Pup plasma levels of trichloroacetic acid, however, were as high as 30 and 15% of the maternal exposure for drinking water and inhalation exposures, respectively.
From page 342...
... For example, the multistage model predicts additivity of excess risks at low doses, even in the presence of interactive effects (NRC, 1988~. Similarly, the multiplicative relative risk model leads to additivity of excess risks at low doses (Krewski et al., 1989~.
From page 343...
... Preschool children of low socioeconomic status have been found to have lower dietary intakes, lower biochemical indices, and smaller physical size for their age than children of higher socioeconomic status (Owen and Frankle, 1986~. Because of compromised health status, poor children are probably more susceptible to any toxic insult, including pesticide exposure.
From page 344...
... Species conversion of dietary intakes per unit of body weight are normally based on adult body weights and food consumption data (McColl, 1989~. Infants and children are unique in a number of ways (see Chapters 2 and 3~.
From page 345...
... In the classical interpretation of the multistage model, the increase cannot exceed a factor of k, the number of stages in the biological system under study. With the twostage model, however, the increased risk can be substantial when the chemical greatly increases the proliferation rate of the initiated cell population.
From page 346...
... If these cases are identified, then parents and other adults concerned can be notified of the possible toxic effects that may be encountered with Deet exposure.
From page 347...
... inhibitors, antiepileptic drugs, other drugs that act on the central nervous system (centrally acting drugs) , propranolol and digoxin, and drugs that alter hepatic blood flow might be of concern.
From page 348...
... Although thiram residues in food are likely to be low, the potential susceptibility for children taking methylphenidate should be of concern. Children taking medication for heart disease might also be at increased risk.
From page 349...
... C arcino gene s is Factors That Might Increase Risk of Cancer Among Infants and Children When subjected to the same low levels of pesticide residues in food measured as parts per million (ppm) , infants and children may be at greater cancer risk than adults for several reasons.
From page 350...
... Potato i , _ , , I 0 20 40 60 Lettuce 20 40 60 FIGURE 8-1 Consumption rates for apple juice, potato, tomato, and lettuce by age. SOURCE: Murdoch et al., 1992.
From page 351...
... Multiplication of the anticipated level of exposure by the unit risk factor leads to an estimate of cancer risk. Effects of Age-Dependent Exposures Methods for estimating lifetime cancer risk when the level of exposure varies over time have been investigated by Crump and Howe (1984)
From page 352...
... in the target tissue at time t as well as the net birthrate 8~) of initiated cells that have sustained the first mutation as a function of time t.
From page 353...
... This implies that the actual lifetime cancer risk due to the presence of residues of a pesticide found in apple juice will be more than 3 times that calculated on the basis of a LADD obtained by amortization of the cumulative lifetime exposure. Assuming a constant daily lifetime expo
From page 354...
... Examination of Tables 8-2 and 8-3 reveals several important findings. First, the largest correction factors C increase with the number of stages k in the multistage model and the cumulative net birth rate of initiated cells in the two-stage model.
From page 355...
... In this example, exposure depends on both food consumption patterns and pesticide residue levels, whereas relative effectiveness is determined by the model of carcinogenesis used. For illustration purposes, if one assumes that pesticide applications produce constant levels of residues in food over time, then the only factors that affect exposure levels are changes in food consumption.
From page 356...
... Even for th = -10, however, the PCLRup to age 10 exceeds 56%. (The parameter th represents the cumulative net birth rate of initiated cells up to t = 70 years of age, and provides a convenient indicator of the rate of proliferation of initiated cells.)
From page 357...
... can be expressed as follows: 70 LR= ~ LR', t=1 where LR~=(d~r~P) /70 denotes the contribution to the lifetime risk at years of age and P is a measure of carcinogenic potency such as the unit risk factor qua based on the linearized multistage model.
From page 358...
... . 0 10 20 30 40 50 60 70 O 10 0 08 0 06 0 04 0 02 k=4; r=4 O - ~=~_~ 0 10 20 30 40 50 60 70 FIGURE 8-3 Multipliers used to obtain annualized contr~butuion to lifetime risk.
From page 359...
... In particular, the level of risk depends on individual food consumption patterns, levels of pesticide residues in foods as consumed by infants and children, and the toxicological potency of the pesticide. A comprehensive analysis of the potential risks to infants and children exposed to pesticides in their diets requires consideration of all these factors, as well as any unique characteristics of infants and children relative to adults.
From page 360...
... Recommendations · Additional data on the food consumption patterns of infants and children are needed. Current data indicate that infants and children consume much more of certain foods on a body weight basis than do adults.
From page 361...
... · Physiological and biochemical characteristics of infants and children that influence metabolism and disposition need to be considered in risk assessment. Physiological parameters such as tissue growth rates and biochemical parameters such as enzyme induction may affect the response of infants and children to pesticide residues in food.
From page 362...
... In this report, the notion of combining distributions of individual food consumption levels with distributions of pesticide residue levels in food to obtain a distribution of exposure levels was used extensively and is illustrated by the examples presented in Chapter 7. Data on the potency of a particular pesticide (expressed either in terms of a reference dose or measure of carcinogenic potency)
From page 363...
... 1985. Multistage models of carcinogenesis.
From page 364...
... 1984. The multistage model with a time-dependent dose pattern: Applications to carcinogenic risk assessment.
From page 365...
... 1989. Physiologically based pharmacokinetic modeling of the pregnant rat: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.
From page 366...
... 1984. A carcinogenic potency database of the standardized results of animal bioassays.
From page 367...
... Pp. 196-214 in Scientific Issues in Quantitative Cancer Risk Assessment, S.H.
From page 368...
... 1993. Correlation between carcinogenic potency and the maximum tolerated dose: Implications for risk assessment.
From page 369...
... 1988. A stochastic two-stage model for cancer risk assessment.
From page 370...
... 1984. The TD50: A proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments.
From page 371...
... 1987. Biologically motivated cancer risk models.
From page 372...
... 1984. Use of acute toxicity to estimate carcinogenic risk.


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