The Role of Cancer Risk in the Regulation of Industrial Pollution

The extent of carcinogen regulation under existing U.S. environmental statutes is assessed by developing measures of the scope and stringency of regulation. While concern about cancer risk has played an important political role in obtaining support for pollution control programs, it has not provided the predominant rationale for most regulatory actions taken to date. Less than 20% of all standards established to limit concentrations of chemicals in various media address carcinogens. Restrictions on chemical use are more frequently based on concerns about noncancer human health or ecological effects. Of the chemicals in commercial use which have been identified as potential human carcinogens on the basis of rodent bioassays, only a small proportion are regulated. There is an inverse relationship between the scope of regulatory coverage and the stringency of regulatory requirements: the largest percentages of identified carcinogens are affected by the least stringent requirements, such as information disclosure. Standards based on de minimis cancer risk levels have been established for only 10% of identified carcinogens and are restricted to one medium: water. Complete bans on use have affected very few chemicals. The general role that carcinogenicity now plays in the regulatory process is not dramatically different from that of other adverse human health effects: if a substance is identified as a hazard, it may eventually be subject to economically achievable and technically feasible restrictions.     

EDB: A Case Study in Communicating Risk

This is a report on the Environmental Protection Agency's (EPA's) efforts to communicate with the public about the risks of ethylene dibromide (EDB), what the agency said it was doing about these risks and what information the public actually received through television and newspapers. Although special in many ways, the EDB case illustrates the problems that regulatory agencies have when they must take regulatory action and assure the public that the risks in question are being dealt with adequately. It also illustrates issues that the press faces. Above all, it illustrates the barriers to communication presented by the different perspectives of regulatory agencies and individuals and the types of information they each are most interested in.     

New Approaches in Risk Assessment for Carcinogens

Methods are needed to improve the ability of biomonitoring and epidemiological studies to identify potential carcinogenic hazards and to quantify human risk. The limitations of pharmacokinetic models can be mitigated by the direct measurement of molecular markers of biologically effective dose of carcinogen. Parallel animal and human studies are recommended as a means of validating these markers.     

A Quantitative Analysis of Factors Affecting PELs and TLVs for Carcinogens

For carcinogens, this paper provides a quantitative examination of the roles of potency and weight-of-evidence (WOE) in setting permissible exposure limits (PELs) at the U.S. Occupational Safety and Health Administration (OSHA) and threshold limit values (TLVs) at the private American Conference of Governmental Industrial Hygienists (ACGIH). On normative grounds, both of these factors should influence choices about the acceptable level of exposures. Our major objective is to examine whether and in what ways these factors have been considered by these organizations. A lesser objective is to identify outliers, which might be candidates for further regulatory scrutiny. Our sample (N=48) includes chemicals for which EPA has estimated a unit risk as a measure of carcinogenic potency and for which OSHA or the ACGIH has a PEL or TLV. Different assessments of the strength of the evidence of carcinogenicity were obtained from EPA, ACGIH, and the International Agency for Research on Cancer. We found that potency alone explains 49% of the variation in PELs and 62% of the variation in TLVs. For the ACGIH, WOE plays a much smaller role than potency. TLVs set by the ACGIH since 1989 appear to be stricter than earlier TLVs. We suggest that this change represents evidence that the ACGIH had responded to criticisms leveled at it in the late 1980s for failing to adopt sufficiently protective standards. The models developed here identify 2-nitropropane, ethylene dibromide, and chromium as having OSHA PELs significantly higher than predicted on the basis of potency and WOE.     

Transgenic Mice as Future Tools in Risk Assessment

Historically, mice have served a routine and useful purpose in the research, development, and testing of biologicals, chemicals, and drugs for efficacy, toxicity, and carcinogenic risk. The literature is replete with examples using mice to study organic compounds both in short-term tests involving tumor initiation and promotion and in long-term experiments dealing with fertility, reproduction, and teratology. During the past two decades, a virtual explosion of advances has occurred in modern biology that includes the discoveries of retroviruses, oncogenes, DNA restriction enzymes, nucleotide sequence analyses, and microinjection techniques. Fusion of these milestones in genetic, molecular, and cell biology with recent developments in mouse embryology has opened novel avenues and methods of experimentation as significant additions to the risk assessment armamentarium that currently uses both prokaryotes and eukaryotes. Some promising directions afforded by transgenic mice as powerful future tools in risk assessment will be summarized below.     

The Indoor Radiological Problem in Perspective

Measures to tighten homes to conserve energy, as are being encouraged and subsidized by federal and state governments, may reduce air infiltration by 20% or more. Standard prudent risk-assessment methodologies predict that, due to increased levels of indoor radon caused by this reduction in ventilation, the added lifetime lung cancer risk to members of the public is of order 200/million people exposed. In situations where the radon source term is unusually high, or extreme reductions in ventilation are made, the added risk can be more than an order of magnitude greater. While these imputed risks are far outside the range that is normally tolerated, no systematic efforts are in progress to mitigate or limit the risk in any way. Furthermore, efforts to determine better the variations in radon source term and the health effects of indoor radon are being deemphasized. The technical background is presented in some detail, and implications with regard to management of risks to the public are discussed.     

Monte Carlo Simulation of Rodent Carcinogenicity Bioassays

In this paper we describe a simulation, by Monte Carlo methods, of the results of rodent carcinogenicity bioassays. Our aim is to study how the observed correlation between carcinogenic potency (beta or 1n2/TD50) and maximum tolerated dose (MTD) arises, and whether the existence of this correlation leads to an artificial correlation between carcinogenic potencies in rats and mice. The validity of the bioassay results depends upon, among other things, certain biases in the experimental design of the bioassays. These include selection of chemicals for bioassay and details of the experimental protocol, including dose levels. We use as variables in our simulation the following factors: (1) dose group size, (2) number of dose groups, (3) tumor rate in the control (zero-dose) group, (4) distribution of the MTD values of the group of chemicals as specified by the mean and standard deviation, (5) the degree of correlation between beta and the MTD, as given by the standard deviation of the random error term in the linear regression of log beta on log (1/MTD), and (6) an upper limit on the number of animals with tumors. Monte Carlo simulation can show whether the information present in the existing rodent bioassay database is sufficient to reject the validity of the proposed interspecies correlations at a given level of stringency. We hope that such analysis will be useful for future bioassay design, and more importantly, for discussion of the whole NCI/NTP program.     

Estimates of the Number of Liver Carcinogens in Bioassays Conducted by the National Toxicology Program

Estimates were made of the numbers of liver carcinogens in 390 long-term bioassays conducted by the National Toxicology Program (NTP). These estimates were obtained from examination of the global pattern of p-values obtained from statistical tests applied to individual bioassays. Representative estimates of the number of liver carcinogens (90% confidence interval in parentheses) obtained in our analysis compared to NTP's determination are as follows: female rats—49 (23, 76), NTP = 30; male rats—88 (59, 116), NTP = 35; female mice—131 (105, 157), NTP = 81; male mice—100 (73, 126), NTP = 61; overall—166 (135, 197), NTP = 108. The estimator from which these estimates were obtained is biased low by an unknown amount. Consequently, this study provides persuasive evidence of the existence of more rodent liver carcinogens than were identified by the NTP.     

Regulation of Carcinogens

We propose a procedure, suitable for regulatory use, for estimating individual and societal risks of carcinogenic materials by using information on interspecies comparisons of carcinogenic potency. The consistent treatment of uncertainties allows evaluation of confidence limits and hence regulatory measures of risk which incorporate safety factors and incentives for better information. Numerical examples are given, together with discussion of the treatment of undetected carcinogens. Applications of the procedure to setting priorities for carcinogenicity testing and to product substitution are mentioned.     

The Tumorigenicity of Mutagenic Contact-Sensitizing Chemicals

The electrophilic nature of some contact sensitizers, that is, chemicals that cause allergic contact dermatitis (ACD), is also characteristic of genotoxic tumorigens. Electrophiles can adduct protein, which is the basis for ACD, as well as DNA, which is the basis for mutagenicity and carcinogenicity. This suggests that some electrophilic contact sensitizers may be genotoxic tumorigens. To further investigate this matter, we evaluated 146 chemicals that had been bioassayed for tumorigenicity and mutagenicity in the National Toxicology Program, with an analysis of structure-activity relationships for contact sensitization. Using the data from this analysis and from other sources, the proportion of the contact sensitizers that were both mutagenic and tumorigenic was found to range from 20% to 28%. This finding suggests that there may be in the order of 90 genotoxic tumorigens for rodents among the approximately 384 chemicals that have been validated as contact sensitizers for humans.