Improving the Regulation of Carcinogens by Expediting Cancer Potency Estimation1

The statutory language of the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65; California Health and Safety Code 25249.5 et seq.) encourages rapid adoption of “no significant risk levels” (NSRLs), intakes associated with estimated cancer risks of no more than 1 in 100,000. Derivation of an NSRL for a carcinogen listed under Proposition 65 requires the development of a cancer potency value. This paper discusses the methodology for the derivation of cancer potencies using an expedited procedure, and provides potency estimates for a number of agents listed as carcinogens under Proposition 65. To derive expedited potency values, default risk assessment methods are applied to data sets selected from an extensive tabulation of animal cancer bioassays according to criteria used by regulatory agencies. A subset of these expedited values is compared to values previously developed by regulatory agencies using conventional quantitative risk assessment and found to be in good agreement. Specific regulatory activities which could be facilitated by adopting similar expedited procedures are identified.     

Assessing Health Risks Associated with DDT Residues in Soils in California: A Proposition 65 Case Study

Population growth in California has increased the pressure to convert agricultural land to commercial, industrial, or residential uses. In the ensuing property transactions, buyers and sellers must address the presence of toxic materials in soils such as pesticides, several of which are known to the State of California to cause cancer under Proposition 65. While this statute does not specifically address soil contaminants, the potential scope of its enforcement is sufficiently broad that owners of former agricultural properties may be obliged to provide warning of exposure to potential buyers, occupants, or construction workers about exposure to residues in soil from pesticide applications. However, Proposition 65 provides no guidance on how to assess exposures to chemicals in soil. The U.S. EPA Risk Assessment Guidance for Superfund (RAGS) provides a method for assessing soil-related exposure pathways that is consistent with the intent of Proposition 65. Using this approach, we have calculated the lifetime average concentrations of DDT in soil corresponding to the no-significant-risk level stipulated under Proposition 65 (1 × 10⁻⁵) for a hypothetical residential exposure scenario. The concentration of DDT in soil corresponding to a no-significant-risk ranges from 7.9-18.8 mg/kg, depending upon which exposure pathways are deemed to be complete for residential land use. It is argued that Proposition 65 forces the assessment and possible cleanup of such a situation through the threat of creating a health risk perception that could affect the market value of a property.     

Point Estimates of Cancer Risk at Low Doses

There has been considerable discussion regarding the conservativeness of low-dose cancer risk estimates based upon linear extrapolation from upper confidence limits. Various groups have expressed a need for best (point) estimates of cancer risk in order to improve risk/benefit decisions. Point estimates of carcinogenic potency obtained from maximum likelihood estimates of low-dose slope may be highly unstable, being sensitive both to the choice of the dose–response model and possibly to minimal perturbations of the data. For carcinogens that augment background carcinogenic processes and/or for mutagenic carcinogens, at low doses the tumor incidence versus target tissue dose is expected to be linear. Pharmacokinetic data may be needed to identify and adjust for exposure-dose nonlinearities. Based on the assumption that the dose response is linear over low doses, a stable point estimate for low-dose cancer risk is proposed. Since various models give similar estimates of risk down to levels of 1%, a stable estimate of the low-dose cancer slope is provided by ŝ = 0.01/ED01, where ED01 is the dose corresponding to an excess cancer risk of 1%. Thus, low-dose estimates of cancer risk are obtained by, risk = ŝ × dose. The proposed procedure is similar to one which has been utilized in the past by the Center for Food Safety and Applied Nutrition, Food and Drug Administration. The upper confidence limit, s , corresponding to this point estimate of low-dose slope is similar to the upper limit, q ₁ obtained from the generalized multistage model. The advantage of the proposed procedure is that ŝ provides stable estimates of low-dose carcinogenic potency, which are not unduly influenced by small perturbations of the tumor incidence rates, unlike ₁.     

Uncertainty in Cancer Risk Estimates

Several existing databases compiled by Gold et al.^(1–3) for carcinogenesis bioassays are examined to obtain estimates of the reproducibility of cancer rates across experiments, strains, and rodent species. A measure of carcinogenic potency is given by the TD₅₀ (daily dose that causes a tumor type in 50% of the exposed animals that otherwise would not develop the tumor in a standard lifetime). The lognormal distribution can be used to model the uncertainty of the estimates of potency (TD₅₀) and the ratio of TD₅₀'s between two species. For near-replicate bioassays, approximately 95% of the TD₅₀'s are estimated to be within a factor of 4 of the mean. Between strains, about 95% of the TD₅₀'s are estimated to be within a factor of 11 of their mean, and the pure genetic component of variability is accounted for by a factor of 6.8. Between rats and mice, about 95% of the TD₅₀'s are estimated to be within a factor of 32 of the mean, while between humans and experimental animals the factor is 110 for 20 chemicals reported by Allen et al.⁽⁴⁾ The common practice of basing cancer risk estimates on the most sensitive rodent species-strain-sex and using interspecies dose scaling based on body surface area appears to overestimate cancer rates for these 20 human carcinogens by about one order of magnitude on the average. Hence, for chemicals where the dose-response is nearly linear below experimental doses, cancer risk estimates based on animal data are not necessarily conservative and may range from a factor of 10 too low for human carcinogens up to a factor of 1000 too high for approximately 95% of the chemicals tested to date. These limits may need to be modified for specific chemicals where additional mechanistic or pharmacokinetic information may suggest alterations or where particularly sensitive subpopu-lations may be exposed. Supralinearity could lead to anticonservative estimates of cancer risk. Underestimating cancer risk by a specific factor has a much larger impact on the actual number of cancer cases than overestimates of smaller risks by the same factor. This paper does not address the uncertainties in high to low dose extrapolation. If the dose-response is sufficiently nonlinear at low doses to produce cancer risks near zero, then low-dose risk estimates based on linear extrapolation are likely to overestimate risk and the limits of uncertainty cannot be established.     

An Evaluation of Risk Estimation Procedures for Mixtures of Carcinogens

The estimation of health risks from exposure to a mixture of chemical carcinogens is generally based on the combination of information from several available single compound studies. The current practice of directly summing the upper bound risk estimates of individual carcinogenic components as an upper bound on the total risk of a mixture is known to be generally too conservative. Gaylor and Chen (1996, Risk Analysis) proposed a simple procedure to compute an upper bound on the total risk using only the upper confidence limits and central risk estimates of individual carcinogens. The Gaylor-Chen procedure was derived based on an underlying assumption of the normality for the distributions of individual risk estimates. In this paper we evaluated the Gaylor-Chen approach in terms of the coverage probability. The performance of the Gaylor-Chen approach in terms the coverages of the upper confidence limits on the true risks of individual carcinogens. In general, if the coverage probabilities for the individual carcinogens are all approximately equal to the nominal level, then the Gaylor-Chen approach should perform well. However, the Gaylor-Chen approach can be conservative or anti-conservative if some or all individual upper confidence limit estimates are conservative or anti-conservative.     

An integrated environmental risk assessment framework for coal-fired power plants: A fuzzy logic approach

This study quantifies the environmental risk of a coal-fired thermal power plant during operation by using environmental monitoring data, site surveys, and documented evidence. The following criteria are assessed: emissions (CO, SO₂, NO_x, PM₁₀), impact on aquatic ecosystem (fish protection at cooling water intake and cooling water discharge temperature), and waste management (fly ash and bottom ash). Fuzzy sets were defined for each criterion, taking environmental regulatory context as an expert judgment. A survey was conducted with multiple stakeholders to determine the relative importance of risk factors. The survey results showed that the most concerned risks are SO₂ and NO_x emissions. The proposed method estimates the risk of each environmental criterion separately and then accumulates them into an environmental risk index (ERI). Accordingly, we assessed the Catalagzi coal-fired power plant, which has been in operation on the Black Sea coast in northwestern Turkey. For this case study, the ERI resulted in a value of 0.78 (on a scale of 0–1), showing high environmental risk to the facility. Moreover, the applicability of the proposed framework was tested in several existing coal-fired power plants using simultaneous measurements. All studied coal-fired power plants in Turkey have unacceptable pollutants (PM₁₀, SO₂, and NO_x) concentration levels indicating high health risk potential. The application of the integrated environmental risk assessment framework showed that new environmental regulations are needed in Turkey to specify more strict emission limits and to monitor CO₂, fine particulate matter emissions, cooling water discharge, and fish protection at cooling water intake.     

Impact of Hazardous Substances Regulations on Small Firms in Delaware and New Jersey

Regulations under the 1990 Amendments to the Clean Air Act impose significant requirements on firms handling hazardous chemicals. The nature of the regulations would suggest that small firms, because of limited resources and other structural limitations, would experience more difficulty complying with the regulations than large firms. To understand the difficulties imposed by the regulations on small firms, we interviewed ten small firms in Delaware and New Jersey, states with existing hazardous regulations similar to those being considered by the U.S. Environmental Protection Agency, and evaluated their responses to state regulations. The impacts of the environmental regulations on the firms and on the risk levels of their businesses are discussed. Propositions for research into small firms compliance are developed. Possible means for reducing the regulatory burden on small firms while enhancing regulatory effectiveness are suggested.     

A Quantitative Estimate of Leukemia Mortality Associated with Occupational Exposure to Benzene3

In 1980, the U.S. Supreme Court vacated a revised occupational standard for benzene, stating that the Occupational Safety and Health Administration (OSHA) had failed to demonstrate that significant health risks existed under the current standard. This decision has been interpreted by OSHA as requiring the consideration of quantitative risk assessments, whenever possible, in the development of regulations for occupational carcinogens. In light of this decision, the available epidemiologic evidence was used to generate a quantitative risk assessment for benzene. Uncertainties regarding the levels and lengths of benzene exposure for the studied cohorts were incorporated into the analysis. Based on the one-hit model, the assessment indicates that a working lifetime exposure to benzene at the current permissible exposure level (10 ppm) poses a substantial excess risk of death from leukemia. This report discusses the calculation of the risk estimates, the basis for relying on certain assumptions, and the inherent limitations of using epidemiologic studies to quantify cancer risks.     

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.     

Partitioning of Dietary Metal Intake—A Metal Dietary Exposure Screening Tool

Detection of heavy metals at trace or higher levels in foods and food ingredients is not unexpected given the widespread unavoidable presence of several metals in nature, coupled with advancement in analytical methods and lowering limits of detection. To assist risk managers with a rapid risk assessment when facing these situations, a metal dietary exposure screening tool (MDEST) was developed. The tool uses food intake rates based on the National Health and Nutrition Examination Survey 2005–2010 consumption data for the U.S. population two+ years and up and for infants age six months to <two years based on the Nestlé Feeding Infants and Toddlers Study, and existing exposure limits for several frequently detected metals (e.g., inorganic arsenic, cadmium, chromium, lead, and mercury). The tool has data entry fields for detected concentrations and includes algorithms that combine metal levels with consumption data to generate screening‐level exposure estimates, which it then compares to MDEST assigned default portions of the exposure limits in the risk characterization module. As a screening‐level tool, the risk assessment output is intentionally conservative, public health protective, and useful for a rapid assessment to set aside issues that are not of concern. Issues that cannot be readily resolved using this screening tool will need to be further evaluated with more refined input data that are tailored to the specific question or situation under consideration.     

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.     

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.     

Assessing Cancer Risks from Short-Term Exposures in Children

For the vast majority of chemicals that have cancer potency estimates on IRIS, the underlying database is deficient with respect to early-life exposures. This data gap has prevented derivation of cancer potency factors that are relevant to this time period, and so assessments may not fully address children's risks. This article provides a review of juvenile animal bioassay data in comparison to adult animal data for a broad array of carcinogens. This comparison indicates that short-term exposures in early life are likely to yield a greater tumor response than short-term exposures in adults, but similar tumor response when compared to long-term exposures in adults. This evidence is brought into a risk assessment context by proposing an approach that: (1) does not prorate children's exposures over the entire life span or mix them with exposures that occur at other ages; (2) applies the cancer slope factor from adult animal or human epidemiology studies to the children's exposure dose to calculate the cancer risk associated with the early-life period; and (3) adds the cancer risk for young children to that for older children/adults to yield a total lifetime cancer risk. The proposed approach allows for the unique exposure and pharmacokinetic factors associated with young children to be fully weighted in the cancer risk assessment. It is very similar to the approach currently used by U.S. EPA for vinyl chloride. The current analysis finds that the database of early life and adult cancer bioassays supports extension of this approach from vinyl chloride to other carcinogens of diverse mode of action. This approach should be enhanced by early-life data specific to the particular carcinogen under analysis whenever possible.     

Comparison of Contact Site Cancer Potency Across Dose Routes: Case Study with Epichlorohydrin*

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.     

Some Limitations of Aggregate Exposure Metrics

Aggregate exposure metrics based on sums or weighted averages of component exposures are widely used in risk assessments of complex mixtures, such as asbestos-associated dusts and fibers. Allowed exposure levels based on total particle or fiber counts and estimated ambient concentrations of such mixtures may be used to make costly risk-management decisions intended to protect human health and to remediate hazardous environments. We show that, in general, aggregate exposure information alone may be inherently unable to guide rational risk-management decisions when the components of the mixture differ significantly in potency and when the percentage compositions of the mixture exposures differ significantly across locations. Under these conditions, which are not uncommon in practice, aggregate exposure metrics may be "worse than useless," in that risk-management decisions based on them are less effective than decisions that ignore the aggregate exposure information and select risk-management actions at random. The potential practical significance of these results is illustrated by a case study of 27 exposure scenarios in El Dorado Hills, California, where applying an aggregate unit risk factor (from EPA's IRIS database) to aggregate exposure metrics produces average risk estimates about 25 times greater - and of uncertain predictive validity - compared to risk estimates based on specific components of the mixture that have been hypothesized to pose risks of human lung cancer and mesothelioma.     

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.     

Reducing Conservatism in Risk Estimation for Mixtures of Carcinogens

The excess cancer risk that might result from exposure to a mixture of chemical carcinogens usually must be estimated using data from experiments conducted with individual chemicals. In estimating such risk, it is commonly assumed that the total risk due to the mixture is the sum of the risks of the individual components, provided that the risks associated with individual chemicals at levels present in the mixture are low. This assumption, while itself not necessarily conservative, has led to the conservative practice of summing individual upper-bound risk estimates in order to obtain an upper bound on the total excess cancer risk for a mixture. Less conservative procedures are described here and are illustrated for the case of a mixture of four carcinogens.     

Fundamentals of Health Risk Assessment. Use,Derivation, Validity and Limitations of Safety Indices

We investigated the way results of human health risk assessments are used, and the theory used to describe those methods, sometimes called the NAS paradigm. Contrary to a key tenet of that theory, current methods have strictly limited utility. The characterizations now considered standard, Safety Indices such as Acceptable Daily Intake, Reference Dose, and so on, usefully inform only decisions that require a choice between two policy alternatives (e.g., approve a food additive or not), decided solely on the basis of a finding of safety. Risk is characterized as the quotient of one of these Safety Indices divided by an estimate of exposure: a quotient greater than one implies that the situation may be considered safe. Such decisions are very widespread, both in the U. S. federal government and elsewhere. No current method is universal; different policies lead to different practices, for example, in California's Proposition 65, where statutory provisions specify some practices. Further, an important kind of human health risk assessment is not recognized by this theory: this kind characterizes risk as likelihood of harm, given estimates of exposure consequent to various decision choices. Likelihood estimates are necessary whenever decision makers have many possible decision choices and must weigh more than two societal values, such as in EPA's implementation of conventional air pollutants. These estimates can not be derived using current methods; different methods are needed. Our analysis suggests changes needed in both the theory and practice of human health risk assessment, and how what is done is depicted.     

Health Risks of PCB Spills from Electrical Equipment

The Southern California Edison Company (SCE) has instituted a series of control strategies designed to minimize human exposure to polychlorinated biphenyls (PCBs) in electrical equipment used on its system. This paper describes a method of analyzing PCB risks using conservative estimates of human intake of PCBs originating from accidental spills from electrical equipment. The PCB releases from the Edison system were determined. The fate of these releases in soil, air, and water was analyzed to determine how much material reaches human receptors. The air and water pathways were determined to be the most likely candidates for the exposure and risk considerations. PCB intake via ingestion of soil at the spill site was neglected as an exposure pathway. Equipment spills without controls resulted in at the most 2 ng/day human intake of PCBs via the water exposure pathway. This was determined to be negligible in comparison with intake rates used in conjunction with the setting of food tolerance levels based on fish being the main dietary pathway of human exposure. The inhalation exposure of the hundred or so persons in the immediate vicinity of a spill was determined to equal the PCB intakes of the fish-eating subpopulation analyzed by the Food and Drug Administration for 2 ppm tolerance standard in the case of no controls or cleanup. Current cleanup procedures assure that even the persons in the immediate area are well below the intake of the subjects in the fish contamination analysis. All exposures were well below a "virtual safe dose" level estimated in the fish tolerance study.