Carcinogenic Mixtures

Human populations are generally exposed simultaneously to a number of toxicants present in the environment, including complex mixtures of unknown and variable origin. While scientific methods for evaluating the potential carcinogenic risks of pure compounds are relatively well established, methods for assessing the risks of complex mixtures are somewhat less developed. This article provides a report of a recent workshop on carcinogenic mixtures sponsored by the Committee on Toxicology of the U.S. National Research Council, in which toxicological, epidemiological, and statistical approaches to carcinogenic risk assessment for mixtures were discussed. Complex mixtures, such as diesel emissions and tobacco smoke, have been shown to have carcinogenic potential. Bioassay-directed fractionation based on short-term screening test for genotoxicity has also been used in identifying carcinogenic components of mixtures. Both toxicological and epidemiological studies have identified clear interactions between chemical carcinogens, including synergistic effects at moderate to high doses. To date, laboratory studies have demonstrated over 900 interactions involving nearly 200 chemical carcinogens. At lower doses, theoretical arguments suggest that risks may be near additive. Thus, additivity at low doses has been invoked as as a working hypothesis by regulatory authorities in the absence of evidence to the contrary. Future studies of the joint effects of carcinogenic agents may serve to elucidate the mechanisms by which interactions occur at higher doses.     

Science Policy Choices and the Estimation of Cancer Risk Associated with Exposure to TCDD

United States regulatory agencies use no-threshold models for estimating carcinogenic risks. Other countries use no-threshold models for carcinogens that are genotoxic and threshold models for carcinogens that are not genotoxic, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD or "dioxin"). The U.S. Environmental Protection Agency has proposed a revision of the carcinogenic potency estimate for TCDD that is based on neither a threshold nor a no-threshold model; instead, it is a compromise between risk numbers generated by the two irreconcilably different models. This paper discusses the revision and its implications.     

Characterizing Dose-Response Relationships in Multiple Cancer Bioassays

In the evaluation of chemical compounds for carcinogenic risk, regulatory agencies such as the U.S. Environmental Protection Agency and National Toxicology Program (NTP) have traditionally fit a dose-response model to data from rodent bioassays, and then used the fitted model to estimate a Virtually Safe Dose or the dose corresponding to a very small increase (usually 10(-6)) in risk over background. Much recent interest has been directed at incorporating additional scientific information regarding the properties of the specific chemical under investigation into the risk assessment process, including biological mechanisms of cancer induction, metabolic pathways, and chemical structure and activity. Despite the fact that regulatory agencies are currently poised to allow use of nonlinear dose-response models based on the concept of an underlying threshold for nongenotoxic chemicals, there have been few attempts to investigate the overall relationship between the shape of dose-response curves and mutagenicity. Using data from an historical database of NTP cancer bioassays, the authors conducted a repeated-measures Analysis of the estimated shape from fitting extended Weibull dose-response curves. It was concluded that genotoxic chemicals have dose-response curves that are closer to linear than those for nongenotoxic chemicals, though on average, both types of compounds have dose-response curves that are convex and the effect of genotoxicity is small.     

Quantifying Uncertainty in a Risk Assessment Using Human Data

A call for risk assessment approaches that better characterize and quantify uncertainty has been made by the scientific and regulatory community. This paper responds to that call by demonstrating a distributional approach that draws upon human data to derive potency estimates and to identify and quantify important sources of uncertainty. The approach is rooted in the science of decision analysis and employs an influence diagram, a decision tree, probabilistic weights, and a distribution of point estimates of carcinogenic potency. Its results estimate the likelihood of different carcinogenic risks (potencies) for a chemical under a specific scenario. For this exercise, human data on formaldehyde were employed to demonstrate the approach. Sensitivity analyses were performed to determine the relative impact of specific levels and alternatives on the potency distribution. The resulting potency estimates are compared with the results of an exercise using animal data on formaldehyde. The paper demonstrates that distributional risk assessment is readily adapted to situations in which epidemiologic data serve as the basis for potency estimates. Strengths and weaknesses of the distributional approach are discussed. Areas for further application and research are recommended.     

Use of Acute Toxicity to Estimate Carcinogenic Risk

Data on the effects of human exposure to carcinogens are limited, so that estimation of the risks of carcinogens must be obtained indirectly. Current risk estimates are generally based on lifetime animal bioassays which are expensive and which take more than two years to complete. We here show how data on acute toxicity can be used to make a preliminary estimate of carcinogenic risk and give an idea of the uncertainty in that risk estimate. The estimates obtained are biased upwards, and so are useful for setting interim standards and determining whether further study is worthwhile. A general scheme which incorporates the use of such estimates is outlined, and it is shown by example how adoption of the procedures suggested could have prevented regulatory hiatus in the past.     

IPO发行制度与信息披露质量——基于保荐制实施与否的比较

本文针对近年来国内IPO公司信息披露质量不尽人意的现状,综合考虑拟上市公司、保荐人和监管部门之间的委托代理关系,采用信息不对称问题的研究框架比较了有无保荐制的发行制度下的社会效益最优模型。理论上,通过求解各模型的均衡解并对结果进行比较发现,在适宜的监管函数下保荐制能够一定程度上提高拟上市公司的信息披露质量。然而通过实证分析发现,目前国内IPO保荐制在提高信息披露质量方面表现堪忧,主要原因在于监管行为的力度不足以对各方参与人形成有效制约。     

Risk Assessment for Aflatoxin: I. Metabolism of Aflatoxin B1 by Different Species

A comparison of the generation and detoxification of reactive aflatoxin B1 metabolites in different species may elucidate why animal species vary widely in sensitivity to aflatoxin B1 carcinogenicity, in addition to offering some perspective on how sensitive man may be to the carcinogenic effects of this mycotoxin. Scientific literature comparing the ability of cellular fractions from different species to metabolize aflatoxin B1 is reviewed. However, in vitro studies exclude components for multiple metabolic pathways, eliminating the possibility of competition between metabolic activation and detoxification. Quantification of metabolic activation by different species from these studies is therefore limited. The species-specific carcinogenic potency of aflatoxin B1 may be reflected in levels of aflatoxin B1-DNA adducts generated in vivo. The current paucity of quantitative information on human DNA adduct levels does not permit comparisons between different species on this basis.     

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.     

团队防御型调节焦点对新产品创造力的双刃剑效应

基于调节焦点理论和团队过程视角,构建了团队防御型调节焦点、信息共享度通过团队活力和团队反思影响新产品创造力的被调节的双通道中介模型。实证研究表明:团队活力中介了防御型调节焦点和新产品创造力的负向间接关系;团队反思中介了防御型调节焦点和新产品创造力的正向间接关系;信息共享度削弱了团队防御型调节焦点对团队活力的负向影响;信息共享度削弱了团队活力在防御型调节焦点和新产品创造力之间的中介作用;团队信息共享度增强了团队防御型调节焦点对团队反思的正向影响;团队信息共享度增强了团队反思在防御型调节焦点和新产品创造力之间的中介作用。     

What to Do at Low Doses: A Bounding Approach for Economic Analysis

To quantify the health benefits of environmental policies, economists generally require estimates of the reduced probability of illness or death. For policies that reduce exposure to carcinogenic substances, these estimates traditionally have been obtained through the linear extrapolation of experimental dose-response data to low-exposure scenarios as described in the U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment (1986). In response to evolving scientific knowledge, EPA proposed revisions to the guidelines in 1996. Under the proposed revisions, dose-response relationships would not be estimated for carcinogens thought to exhibit nonlinear modes of action. Such a change in cancer-risk assessment methods and outputs will likely have serious consequences for how benefit-cost analyses of policies aimed at reducing cancer risks are conducted. Any tendency for reduced quantification of effects in environmental risk assessments, such as those contemplated in the revisions to EPA's cancer-risk assessment guidelines, impedes the ability of economic analysts to respond to increasing calls for benefit-cost analysis. This article examines the implications for benefit-cost analysis of carcinogenic exposures of the proposed changes to the 1986 Guidelines and proposes an approach for bounding dose-response relationships when no biologically based models are available. In spite of the more limited quantitative information provided in a carcinogen risk assessment under the proposed revisions to the guidelines, we argue that reasonable bounds on dose-response relationships can be estimated for low-level exposures to nonlinear carcinogens. This approach yields estimates of reduced illness for use in a benefit-cost analysis while incorporating evidence of nonlinearities in the dose-response relationship. As an illustration, the bounding approach is applied to the case of chloroform exposure.     

Does restricted stock turn CEOs into risk-averse managers? Insights from the regulatory focus theory

Restricted stock awards carry upside and downside risks for CEOs. We follow a socio-cognitive perspective by suggesting that awards of restricted stock are viewed as potential gains or potential losses depending on each CEO's dominant regulatory focus. Regulatory focus, therefore, helps determine how a CEO responds to restricted stock awards. We also propose that the moderating effect of regulatory focus strengthens as firm complexity increases and as CEO tenure lengthens, because complexity and tenure both increase CEOs' reliance on heuristic information processing. Specifically, complexity restricts a CEO's cognitive capacity for thoughtful deliberation during decision making, and tenure affects a CEO's motivation to search for and process information thoroughly. We find general support for the hypotheses and discuss the implications of our findings for future research and practice.     

A Method for Estimating Lifetime Cancer Risks from Limited Epidemiologic Data

Partly because of the poor quality of exposure information on humans, most lifetime carcinogenic risk assessments have been based on animal data. There are, however, surrogate measures for exposure that have not been fully utilized. One of these is duration of exposure where data on mean exposure levels are available. A method is presented for the use of such data, and the method is illustrated by developing a risk assessment from the available epidemiologic literature on gasoline and kidney cancer. This risk assessment is fairly consistent across studies and close to a risk assessment based upon an experiment with rats. While there needs to be much improvement in the quality of environmental data available to epidemiologists, it is possible that a number of risk assessments can be made from existing epidemiologic data and efforts directed away from extrapolation from animal data.     

A Distributional Approach to Characterizing Low-Dose Cancer Risk

Since cancer risk at very low doses cannot be directly measured in humans or animals, mathematical extrapolation models and scientific judgment are required. This article demonstrates a probabilistic approach to carcinogen risk assessment that employs probability trees, subjective probabilities, and standard bootstrapping procedures. The probabilistic approach is applied to the carcinogenic risk of formaldehyde in environmental and occupational settings. Sensitivity analyses illustrate conditional estimates of risk for each path in the probability tree. Fundamental mechanistic uncertainties are characterized. A strength of the analysis is the explicit treatment of alternative beliefs about pharmacokinetics and pharmacodynamics. The resulting probability distributions on cancer risk are compared with the point estimates reported by federal agencies. Limitations of the approach are discussed as well as future research directions.     

Risk Assessment for Aflatoxin: An Evaluation Based on the Multistage Model

Lifetime cancer potency of alfatoxin was assessed based on the Yeh et al. study from China in which both aflatoxin exposure and hepatitis B prevalence were measured. This study provides the best available information for estimating the carcinogenic risk posed by aflatoxin to the U.S. population. Cancer potency of aflatoxin was estimated using a biologically motivated risk assessment model. The best estimate of aflatoxin potency was 9 (mg/kg/day)⁻¹ for individuals negative for hepatitis B and 230 (mg/kg/day)⁻¹ for individuals positive for hepatitis B.     

Public Perceptions of Regulatory Costs,Their Uncertainty and Interindividual Distribution

Public perceptions of both risks and regulatory costs shape rational regulatory choices. Despite decades of risk perception studies, this article is the first on regulatory cost perceptions. A survey of 744 U.S. residents probed: (1) How knowledgeable are laypeople about regulatory costs incurred to reduce risks? (2) Do laypeople see official estimates of cost and benefit (lives saved) as accurate? (3) (How) do preferences for hypothetical regulations change when mean‐preserving spreads of uncertainty replace certain cost or benefit? and (4) (How) do preferences change when unequal interindividual distributions of hypothetical regulatory costs replace equal distributions? Respondents overestimated costs of regulatory compliance, while assuming agencies underestimate costs. Most assumed agency estimates of benefits are accurate; a third believed both cost and benefit estimates are accurate. Cost and benefit estimates presented without uncertainty were slightly preferred to those surrounded by “narrow uncertainty” (a range of costs or lives entirely within a personally‐calibrated zone without clear acceptance or rejection of tradeoffs). Certain estimates were more preferred than “wide uncertainty” (a range of agency estimates extending beyond these personal bounds, thus posing a gamble between favored and unacceptable tradeoffs), particularly for costs as opposed to benefits (but even for costs a quarter of respondents preferred wide uncertainty to certainty). Agency‐acknowledged uncertainty in general elicited mixed judgments of honesty and trustworthiness. People preferred egalitarian distributions of regulatory costs, despite skewed actual cost distributions, and preferred progressive cost distributions (the rich pay a greater than proportional share) to regressive ones. Efficient and socially responsive regulations require disclosure of much more information about regulatory costs and risks.     

The Potential Effects of Recall Bias and Selection Bias on the Epidemiological Evidence for the Carcinogenicity of Glyphosate

Glyphosate is a widely used herbicide worldwide. The International Agency for Research on Cancer in 2015 declared that glyphosate is probably carcinogenic to humans, noting a positive association for non-Hodgkin lymphoma (NHL). The principal human data on glyphosate and NHL come from five case–control studies and two cohort studies. The case–control studies are at risk of recall bias resulting from information on exposure to pesticides being collected from cases and controls based on their memories. In addition, two of the case–control studies are additionally at risk of a form of selection bias that can exacerbate the effect of recall bias. Both biases are in the direction of making glyphosate appear carcinogenic. If odds ratios (ORs) are not biased and a pesticide plays no role in causing NHL, the probability that an OR for that pesticide is greater than 1.0 is approximately 0.5. The fractions of ORs for pesticides other than glyphosate that are greater than 1.0 in the case–control studies are 0.90 (n = 92), 0.90 (n = 152), 0.93 (n = 59), 0.76 (n = 140), and 0.53 (n = 54), the first two from studies that are at risk for both types of bias. In the two cohort studies, which are not subject to these biases, the comparable fractions for relative risks for all cancers are 0.51 (n = 70) and 0.48 (n = 158). These results comply closely with what would be expected if evidence for carcinogenicity of glyphosate in these studies results from statistical bias in the case–control studies.     

When Does Poor Governance Presage Biosecurity Risk?

Border inspection, and the challenge of deciding which of the tens of millions of consignments that arrive should be inspected, is a perennial problem for regulatory authorities. The objective of these inspections is to minimize the risk of contraband entering the country. As an example, for regulatory authorities in charge of biosecurity material, consignments of goods are classified before arrival according to their economic tariff number. This classification, perhaps along with other information, is used as a screening step to determine whether further biosecurity intervention, such as inspection, is necessary. Other information associated with consignments includes details such as the country of origin, supplier, and importer, for example. The choice of which consignments to inspect has typically been informed by historical records of intercepted material. Fortunately for regulators, interception is a rare event; however, this sparsity undermines the utility of historical records for deciding which containers to inspect. In this article, we report on an analysis that uses more detailed information to inform inspection. Using quarantine biosecurity as a case study, we create statistical profiles using generalized linear mixed models and compare different model specifications with historical information alone, demonstrating the utility of a statistical modeling approach. We also demonstrate some graphical model summaries that provide managers with insight into pathway governance.     

Correlation Between Carcinogenic Potency of Chemicals in Animals and Humans

Twenty-three chemicals were selected for comparison of the carcinogenic potencies estimated from epidemiological data to those estimated from animal carcinogenesis bioassays. The chemicals were all those for which reasonably strong evidence of carcinogenicity could be found in humans or animals and for which suitable data could be obtained for quantifying carcinogenic potencies in both humans and animals. Many alternative methods of analyzing the bioassay data were investigated. Almost all of the methods yielded potency estimates that were highly correlated with potencies estimated from epidemiological data; correlations were highly statistically significant (p less than 0.001), with the corresponding correlation coefficients ranging as high as 0.9. These findings provide support for the general use of animal data to evaluate carcinogenic potential in humans and also for the use of animal data to quantify human risk.