Drinking Water and Health, Volume 3 (1980) / Chapter Skim
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III Problems of Risk Estimation
III Problems of Risk Estimation
Pages 25-66
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From page 25... ...
The other, which has been used to estimate the risk to the population as a whole from low doses of radiation, is based on extrapolation of experimental dose-effect curves to lower dose levels where no data existed. This is called the "risk estimate" approach.
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From page 26... ...
has been considered for use with chronic oral toxicity data to estimate an acceptable risk to the exposed population. Unfortunately, none of these safety factors, including the most conservative, has any relevant experimental verification in heterogeneous populations that are analogous to humans likely to be exposed acutely to contaminants in drinking water.
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From page 27... ...
, who simulated the effect of antimetabolites on de-novo DNA synthesis, and observed considerable joint action ranging from potentiation through additivity to antagonism. In general, there is not likely to be sufficient information on mixtures of environmental contaminants.
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Ironically, the best quantitative data on interspecies toxicology, including humans, have been obtained from work on developing and evaluating anticancer drugs. These are usually cytotoxic agents that involve a variety of mechanisms of action.
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The use of safety (or uncertainty) factors in extrapolating animal toxicity data to acceptable exposure levels for humans has been the cornerstone of regulatory toxicology.
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From page 30... ...
They recognized that animal species, strain, and sex differences, variations in susceptibility among exposed individuals, insufficient laboratory animal data, and a number of other matters must be considered when arriving at the ADI. Food additives or other er~vironmental contaminants may be ingested by people of all ages throughout their lives.
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From page 31... ...
One approach is extrapolation to low doses from high dose animal toxicity data that show a dose response. The subcommittee has examined the potential of such extrapolation for providing estimates of noncarcinogenic toxic effects of drinking water contaminants at the low exposure levels that were determined by the ADI calculations in Drinking Water and Health (National Academy of Sciences, 19771.
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From page 32... ...
This ADI was translated to a total lifetime dose in mg/kg-days for humans based on an assumption of a total population dietary intake of 666 kg/yr (Lehman, 1962) for a 70-kg human over a 70-year lifetime, producing 57 mg/kg-days of exposure.
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From page 33... ...
This interval indicates that the extrapolated risk lies between 3 x 10-8 and 0.095, an interval so wide as to suggest that little is known quantitatively about the level of risk. This example shows that applying dose-response extrapolation techniques when the data are limited in experimental dose levels and sample sizes will not yield precise risk estimates.
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From page 34... ...
~4 3 C~ .` C'7 .~ ~: o oo .o ~ m :S e~ ~> E ~o 3 u, V, + ~, ~ .:Y U' _ o 62, .5 o + oo 3 C~ E~ ~ o ~, ~ ~ _% 888 , .
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From page 35... ...
Although the female rat appears to be the most sensitive of these three groups, the two dose-response models give quite different results. At a daily exposure level of 0.0001 ~g/kg, the average thymus weight of the most sensitive animal, the female rat, is estimated to be either 99.81% or 99.13% that of the unexposed animals.
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From page 36... ...
Consequently, in the absence of such data the application of safety factors to no-observed-effect levels that have been derived from laboratory animal toxicity data is the most feasible and currently acceptable method for the determination of human exposure limits to noncarcinogenic environmental contaminants. To incorporate differential measures of uncertainty in these ADI calculations, the Safe Drinking Water Committee (National Academy of Sciences, 1977)
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From page 37... ...
Thus, applying ADI methods to carcinogens instead of risk estimates may very well be misleading with regard to regulatory actions. MODELS FOR LOW DOSE CARCINOGENIC RISK ESTIMATION Dichotomous Response Models In many quantitative theories of carcinogenesis it is assumed that the process consists of one or more stages at the cellular level beginning with a single cell somatic mutation at which point the cancer is initiated.
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From page 38... ...
38 Cal .
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From page 40... ...
Under the assumption that the true dose-response relationship is convex (positive second derivative with the dose on the abscissa) in the low dose region, linear extrapolation from an experimental dose in this region of convexity will provide an overestimate to the true low dose risk.
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From page 41... ...
have suggested that a modified version of this model be used for extrapolation of carcinogenesis bioassays from high to low doses. They stated that since the normal probability model is not usually true at the extremes, i.e., there is often more probability mass in the tails of the distribution than the normal model would predict, then the slope of the relationship between the log dose and the probit of response will flatten out and become less steep as the dose level decreases.
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From page 42... ...
argued in favor of a multievent theory of radiation-induced carcinogenesis which involves both a linear and quadratic dependence upon dose. He also suggested that the possibility of cell killing at high dose levels be included in the model.
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From page 43... ...
defined this time between initial exposure and clinical appearance of the disease as the latent period. These data add information that aids the determination of the dose-response relationship, especially in experimental situations in which the response rates at the high dose levels are close to lOO~o.
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From page 44... ...
= 1; however, because of competing risks such as death without evidence of the disease, the subject may be removed from observation before the response occurs. This assumption is probably more valid for chronic exposure than for acute exposure.
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From page 45... ...
These restrictions reduce the usefulness of such approaches for high to low dose extrapolation. When using a model that is fit to the experimental result and then used for extrapolation, it is assumed that the dose-response relationship observed at these high dose levels will continue to hold throughout the entire spectrum of exposure levels.
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From page 46... ...
46 DRINKING WATER AND H"LTH relating concentration with eject depend on the mechanism. It is commonly assumed in pharmacology that the biochemical effect of a reversible inhibitor depends on the existing free concentration of drug at the site of action.
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From page 47... ...
The kinetic implications and consequences for extrapolation of animal data to humans were discussed by Gillette (1976, 19771. Most of the emphasis has been placed on organic chemicals since comparable concepts relating to precise chemical species of inorganic complexes in biological systems are not well studied.
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From page 48... ...
to form an activated complex, X D can also react irreversibly with a deactivator, T
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From page 49... ...
Adolph (1949) correlated a large number of quantitative properties of mammals with body weight.
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From page 50... ...
( 1966) determined that 3,~ benzpyrene, pentobarbital, and 3-methyl-4-monomethylaminoazobenzene are metabolized more slowly by human liver enzymes than by preparations from male rats; dealkylation of acetophenetidin was more rapid with human liver preparations.
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From page 51... ...
INTERACTION IN RISK ESTIMATION Most toxicological studies of the effects of chemicals on mammals are performed using one chemical at a time as the toxicant. However, the joint action of chemicals in the environment must also be addressed.
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From page 52... ...
Bliss also used the probit dose-response model to relate the dose levels of the two toxicants to the probability of response. Plackett and Hewlett, in a series of papers (Plackett and Hewlett, 1952; Hewlett and Plackett, 1959, 1964)
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From page 53... ...
The estimation of low exposure risk in a multifactor situation will be highly dependent upon the mechanisms of action by the joint agents. The models of joint toxic action could be of benefit in the risk
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From page 54... ...
High dose to low dose extrapolation for individual agents is an unresolved problem filled with many unknowns, and extrapolation of the actions of joint agents contains an additional major source of uncertainty. Epidemiological Risk Assessment Two major problems are encountered in the assessment of human risk based on the results of experimental animal bioassays: (1)
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From page 55... ...
Even with their inherent limitations and difficulties, these types of analytic epidemiological studies provide useful information for assessing the risk from environmental contaminants. However, there are no adequate analytic studies of this nature on the relationship between cancer incidence and exposure to drinking water contaminants.
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From page 56... ...
This is true even at the high dose levels at which effects could be measured. At the low dose levels corresponding to expected human exposures, the attendant number of responses are so small that the performance of experiments with adequate statistical precision would require an inordinate number of laboratory animals.
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From page 57... ...
A limited animal bioassay conducted at dose levels high enough to give observable response rates cannot discriminate among these various models, and these same models are substantively divergent at lower dose levels. These factors present major difficulties for high to low dose extrapolations.
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From page 58... ...
As the mathematical theory predicts (Crump et al., 1976) , the model, assuming background additivity, approaches linearity at low dose levels.
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From page 59... ...
Therefore, its use for extrapolation is consistent with the conservative linear risk estimation. If the precise mechanism of carcinogenesis is represented by a threshold or log-normal dose-response relationship, the multistage model ma, considerably overestimate the risk at low dose levels.
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From page 60... ...
In these cases of noncarcinogenic toxicity, the preferred procedure is to make a risk estimate based on extrapolation to low dose levels from experimental curves obtained from much larger doses where ejects can be readily measured. When such curves are not available, the ADI approach should be used until better data are available.
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From page 61... ...
Presented at the National Institute of Environmental Health Sciences Conference on Extrapolation of Risks to Man from Environmental Toxicants on the Basis of Animal Experiments. Wrightsville Beach, N.C., October 1974.
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From page 62... ...
1978. Low dose extrapolation of animal carcinogenicity data.
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From page 63... ...
1979. Association between chloroform levels in finished drinking water supplies and various site-specific cancer mortality rates.
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Presented at the National Institue of Environmental Health Sciences Conference on Extrapolation of Risks to Man from Environmental Toxicants on the Basis of Animal Experiments. Wrightsville Beach, N.C., October 1974.
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From page 65... ...
1969. An exploration of joint toxic action: twenty-seven industrial chemicals intubated in rats in all possible pairs.
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