Dose-Response and Risk Assessment of Airborne Hexavalent Chromium and Lung Cancer Mortality

This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).     

Using the Biological Two-Stage Model to Assess Risk from Short-Term Exposures

Two assumptions used in risk assessment are investigated: (1) the assumption of fraction of lifetime dose rate assumes that the risk from a fractional lifetime exposure at a given dose rate is equal to the risk from full lifetime exposure at that same fraction of the given dose rate; (2) the assumption of fraction of lifetime risk assumes that the risk from a fractional lifetime exposure at a given dose rate is equal to that same fraction of the risk from full lifetime exposure at the same dose rate. These two assumptions are equivalent when risk is a linear function of dose. Thus both can be thought of as generalizations of the assumption that cancer risk is proportional to the total accumulated lifetime dose (or average daily dose), which is often made to assess the risk from short-term exposures. In this paper, the age-specific cumulative hazard functions are derived using the two-stage model developed by Moolgavkar, Venzon, and Knudson for situations when the exposure occurs during a single period or a single instant. The two assumptions described above are examined for three types of carcinogens, initiator, completer, and promoter, in the context of the model. For initiator and completer, these two assumptions are equivalent in the low-dose region; for a promoter, using the fraction of lifetime risk assumption is generally more conservative than that of the fraction of lifetime dose rate assumption. Tables are constructed to show that the use of either the fraction of lifetime dose rate assumption or the fraction lifetime risk assumption can both underestimate and overestimate the true risk for the three types of carcinogens.     

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.     

Estimation of the Joint Risk from Multiple-Compound Exposure Based on Single-Compound Experiments

In the absence of data from multiple-compound exposure experiments, the health risk from exposure to a mixture of chemical carcinogens is generally based on the results of the individual single-compound experiments. A procedure to obtain an upper confidence limit on the total risk is proposed under the assumption that total risk for the mixture is additive. It is shown that the current practice of simply summing the individual upper-confidence-limit risk estimates as the upper-confidence-limit estimate on the total excess risk of the mixture may overestimate the true upper bound. In general, if the individual upper-confidence-limit risk estimates are on the same order of magnitude, the proposed method gives a smaller upper-confidence-limit risk estimate than the estimate based on summing the individual upper-confidence-limit estimates; the difference increases as the number of carcinogenic components increases.     

Does EPA Underestimate Cancer Risks by Ignoring Susceptibility Differences?

A 2009 report of the National Research Council (NRC) recommended that the U.S. Environmental Protection Agency (EPA) increase its estimates of increased cancer risk from exposure to environmental agents by ～7‐fold, due to an approximate ～25‐fold typical ratio between the median and upper 95th percentile persons’ cancer sensitivity assuming approximately lognormally distributed sensitivities. EPA inaction on this issue has raised concerns that cancer risks to environmentally exposed populations remain systematically underestimated. This concern is unwarranted, however, because EPA point estimates of cancer risk have always pertained to the average, not the median, person in each modeled exposure group. Nevertheless, EPA has yet to explain clearly how its risk characterization and risk management policies concerning individual risks from environmental chemical carcinogens do appropriately address broad variability in human cancer susceptibility that has been a focus of two major NRC reports to EPA concerning its risk assessment methods.     

Risk Assessment for Aflatoxin: III. Modeling the Relative Risk of Hepatocellular Carcinoma

Estimates have been made of the cancer potency of aflatoxin exposure among the U.S. population. Risk modeling is used to assess the dose-response relationship between aflatoxin exposure and primary liver cancer, controlling for hepatitis B virus (HBV), based on data provided by the Yeh et al. study in China. A relative risk model is proposed as a more appropriate alternative to the additive ("absolute" risk) model for transportation of risk coefficients between populations with different baseline rates. Several general relative risk models were examined; the exponential model provided the best fit. The Poisson regression method was used to fit the relative risk model to the grouped data. The effects of exposure to aflatoxin (AFB1) and hepatitis B infection were both found to be statistically significant. The risk of death from liver cancer for those exposed to AFB1 relative to the unexposed population, increases by 0.05% per ng/kg/day exposure of AFB1 (p less than 0.001). The results also indicated a 25-fold increase in the risk of death from liver cancer among those infected with hepatitis B virus, relative to noncarriers (p less than 0.0001). With a hepatitis prevalence rate of 1%, the aflatoxin intake level associated with liver cancer lifetime excess risk of 1 x 10(-5) for the U.S. population was estimated as 253 ng/day, based on a liver cancer baseline rate of 3.4/100,000/yr.     

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.     

A Simple Upper Limit for the Sum of the Risks of the Components in a Mixture

Natural or manufactured products may contain mixtures of carcinogens and the human environment certainly contains mixtures of carcinogens. Various authors have shown that the total risk of a mixture can be approximated by the sum of the risks of the individual components under a variety of conditions at low doses. Under these conditions, summing the individual estimated upper bound risks, as currently often done, is too conservative because it is unlikely that all risks for a mixture are at their maximum levels simultaneously. In the absence of synergism, a simple procedure is proposed for estimating a more appropriate upper bound of the additive risks for a mixture of carcinogens. These simple limits also apply to noncancer endpoints when the risks of the components are approximately additive.     

A Method for Comparing the Impact on Carcinogenicity of Tobacco Products: A Case Study on Heated Tobacco Versus Cigarettes

Comparing the harmful health effects related to two different tobacco products by applying common risk assessment methods to each individual compound is problematic. We developed a method that circumvents some of these problems by focusing on the change in cumulative exposure (CCE) of the compounds emitted by the two products considered. The method consists of six steps. The first three steps encompass dose-response analysis of cancer data, resulting in relative potency factors with confidence intervals. The fourth step evaluates emission data, resulting in confidence intervals for the expected emission of each compound. The fifth step calculates the change in CCE, probabilistically, resulting in an uncertainty range for the CCE. The sixth step estimates the associated health impact by combining the CCE with relevant dose-response information. As an illustrative case study, we applied the method to eight carcinogens occurring both in the emissions of heated tobacco products (HTPs), a novel class of tobacco products, and tobacco smoke. The CCE was estimated to be 10- to 25-fold lower when using HTPs instead of cigarettes. Such a change indicates a substantially smaller reduction in expected life span, based on available dose-response information in smokers. However, this is a preliminary conclusion, as only eight carcinogens were considered so far. Furthermore, an unfavorable health impact related to HTPs remains as compared to complete abstinence. Our method results in useful information that may help policy makers in better understanding the potential health impact of new tobacco and related products. A similar approach can be used to compare the carcinogenicity of other mixtures.     

Combined Effects of Contaminant Desorption and Toxicity on Risk from PAH Contaminated Sediments

A strong inverse correlation was observed between the polycyclic aromatic hydrocarbon (PAH) mass fraction desorbed, a surrogate measure of bioavailability, and relative carcinogenicity, as quantified by potency equivalency factors (PEFs), for two study sediments from the New York/New Jersey Harbor estuary. Because compounds with the highest toxicity, such as dibenz(a,h)anthracene and benzo(a)pyrene (BAP), also tended to be the least rapidly and least extensively desorbed, the U.S. Environmental Protection Agency (EPA) default guidance may dramatically overestimate risk from exposure to PAH-contaminated soils or sediments. A "relative risk index" (RRI) was developed to account for the combined effects of compound-specific bioavailability and toxic potency in estimating excess cancer risk. Using this approach, estimated excess cancer risk may be diminished by as much as a factor of 159 times versus default EPA guidance. Also, the hierarchy of estimated risk between study sediments and among treatment fractions of study sediments differed using the two approaches, implying that the default approach may inaccurately determine site clean-up priorities. The percentage contribution of each potentially carcinogenic priority PAH to total excess cancer risk was computed under various scenarios. In each case, the contribution of BAP to total excess cancer risk was remarkably invariable, for example, ranging from 48% to 52% in one sediment, and 44% to 54% in the other, over four different exposure durations. These results suggest that BAP may be an excellent indexing compound for gauging relative exposure risk across sediments. Other important contributors to total excess cancer risk were benz(a)anthracene and dibenz(a,h)anthracene. Together, these three compounds comprised nearly 90% of total excess cancer risk from all PAHs in every scenario. This integrated RRI approach may enable regulators to more accurately gauge relative risks and make more informed sediment management decisions.     

Exposure to Persistent Organochlorines in Canadian Breast Milk: A Probabilistic Assessment

Exposure to persistent organochlorines in breast milk was estimated probabilistically for Canadian infants. Noncancer health effects were evaluated by comparing the predicted exposure distributions to published guidance values. For chemicals identified as potential human carcinogens, cancer risks were evaluated using standard methodology typically applied in Canada, as well as an alternative method developed under the Canadian Environmental Protection Act. Potential health risks associated with exposure to persistent organochlorines were quantitatively and qualitatively weighed against the benefits of breast-feeding. Current levels of the majority of contaminants identified in Canadian breast milk do not pose unacceptable risks to infants. Benefits of breast-feeding are well documented and qualitatively appear to outweigh potential health concerns associated with organochlorine exposure. Furthermore, the risks of mortality from not breast-feeding estimated by Rogan and colleagues exceed the theoretical cancer risks estimated for infant exposure to potential carcinogens in Canadian breast milk. Although levels of persistent compounds have been declining in Canadian breast milk, potentially significant risks were estimated for exposure to polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans. Follow-up work is suggested that would involve the use of a physiologically based toxicokinetic model with probabilistic inputs to predict dioxin exposure to the infant. A more detailed risk analysis could be carried out by coupling the exposure estimates with a dose–response analysis that accounts for uncertainty.     

Quantitative Assessment of the Risk of Lung Cancer Associated with Occupational Exposure to Refractory Ceramic Fibers

We present the results of a quantitative assessment of the lung cancer risk associated with occupational exposure to refractory ceramic fibers (RCF). The primary sources of data for our risk assessment were two long-term oncogenicity studies in male Fischer rats conducted to assess the potential pathogenic effects associated with prolonged inhalation of RCF. An interesting feature of the data was the availability of the temporal profile of fiber burden in the lungs of experimental animals. Because of this information, we were able to conduct both exposure–response and dose–response analyses. Our risk assessment was conducted within the framework of a biologically based model for carcinogenesis, the two-stage clonal expansion model, which allows for the explicit incorporation of the concepts of initiation and promotion in the analyses. We found that a model positing that RCF was an initiator had the highest likelihood. We proposed an approach based on biological considerations for the extrapolation of risk to humans. This approach requires estimation of human lung burdens for specific exposure scenarios, which we did by using an extension of a model due to Yu. Our approach acknowledges that the risk associated with exposure to RCF depends on exposure to other lung carcinogens. We present estimates of risk in two populations: (1) a population of nonsmokers and (2) an occupational cohort of steelworkers not exposed to coke oven emissions, a mixed population that includes both smokers and nonsmokers.     

Peak Exposures in Epidemiologic Studies and Cancer Risks: Considerations for Regulatory Risk Assessment

We review approaches for characterizing “peak” exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose–response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. We searched the epidemiologic literature on environmental chemicals classified as carcinogens in which cancer risks were described in relation to “peak” exposures. These articles were evaluated to identify some of the challenges associated with defining and describing cancer risks in relation to peak exposures. We found that definitions of peak exposure varied considerably across studies. Of nine chemical agents included in our review of peak exposure, six had epidemiologic data used by the U.S. Environmental Protection Agency (US EPA) in dose–response assessments to derive inhalation unit risk values. These were benzene, formaldehyde, styrene, trichloroethylene, acrylonitrile, and ethylene oxide. All derived unit risks relied on cumulative exposure for dose–response estimation and none, to our knowledge, considered peak exposure metrics. This is not surprising, given the historical linear no‐threshold default model (generally based on cumulative exposure) used in regulatory risk assessments. With newly proposed US EPA rule language, fuller consideration of alternative exposure and dose–response metrics will be supported. “Peak” exposure has not been consistently defined and rarely has been evaluated in epidemiologic studies of cancer risks. We recommend developing uniform definitions of “peak” exposure to facilitate fuller evaluation of dose response for environmental chemicals and cancer risks, especially where mechanistic understanding indicates that the dose response is unlikely linear and that short‐term high‐intensity exposures increase risk.     

Cancer Risk Estimation of Genotoxic Chemicals Based on Target Dose and a Multiplicative Model

A mechanistic model and associated procedures are proposed for cancer risk assessment of genotoxic chemicals. As previously shown for ionizing radiation, a linear multiplicative model was found to be compatible with published experimental data for ethylene oxide, acrylamide, and butadiene. The validity of this model was anticipated in view of the multiplicative interaction of mutation with inherited and acquired growth-promoting conditions. Concurrent analysis led to rejection of an additive model (i.e. the model commonly applied for cancer risk assessment). A reanalysis of data for radiogenic cancer in mouse, dog and man shows that the relative risk coefficient is approximately the same (0.4 to 0.5 percent per rad) for tumours induced in the three species.Doses in vivo, defined as the time-integrated concentrations of ultimate mutagens, expressed in millimol × kg^–1 × h (mMh) are, like radiation doses given in Gy or rad, proportional to frequencies of potentially mutagenic events. The radiation dose equivalents of chemical doses are, calculated by multiplying chemical doses (in mMh) with the relative genotoxic potencies (in rad × mMh^–1) determined in vitro. In this way the relative cancer incidence increments in rats and mice exposed to ethylene oxide were shown to be about 0.4 percent per rad-equivalent, in agreement with the data for radiogenic cancer.Our analyses suggest that values of the relative risk coefficients for genotoxic chemicals are independent of species and that relative cancer risks determined in animal tests apply also to humans. If reliable animal test data are not available, cancer risks may be estimated by the relative potency. In both cases exposure dose/target dose relationships, the latter via macromolecule adducts, should be determined.     

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.     

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.     

Comparative Risk Analysis of Dioxins in Fish and Fine Particles from Heavy-Duty Vehicles

Dioxins and airborne fine particles are both environmental health problems that have been the subject of active public debate. Knowledge on fine particles has increased substantially during the last 10 years, and even the current, lowered levels in the Europe and in the United States appear to be a major public health problem. On the other hand, dioxins are ubiquitous persistent contaminants, some being carcinogens at high doses, and therefore of great concern. Our aim was to (a) quantitatively analyze the two pollutant health risks and (b) study the changes in risk in view of the current and forthcoming EU legislations on pollutants. We performed a comparative risk assessment for both pollutants in the Helsinki metropolitan area (Finland) and estimated the health effects with several scenarios. For primary fine particles: a comparison between the present emission situation for heavy-duty vehicles and the new fine particle emission standards set by the EU. For dioxins: an EU directive that regulates commercial fishing of Baltic salmon and herring that exceed the dioxin concentration limit set for fish meat, and a derogation (= exemption) from the directive for these two species. Both of these two decisions are very topical issues and this study estimates the expected changes in health effects due to these regulations. It was found that the estimated fine particle risk clearly outweighed the estimated dioxin risk. A substantial improvement to public health could be achieved by initiating reductions in emission standards; about 30 avoided premature deaths annually in the study area. In addition, the benefits of fish consumption due to omega-3 exposure were notably higher than the potential dioxin cancer risk. Both regulations were instigated as ways of promoting public health.     

An Enforceable Indoor Air Quality Standard for Environmental Tobacco Smoke in the Workplace1

Environmental tobacco smoke (ETS)has recently been determined by U.S. environmental and occupational health authorities to be a human carcinogen. We develop a model which permits using atmospheric nicotine measurements to estimate nonsmokers’ETS lung cancer risks in individual workplaces for the first time. We estimate that during the 1980s, the U.S. nonsmoking adult population's median nicotine lung exposure (homes and workplaces combined)was 143 micrograms (μg)of nicotine daily, and that most-exposed adult nonsmokers inhaled 1430 μg/day. These exposure estimates are validated by pharmacokinetic modeling which yields the corresponding steady-state dose of the nicotine metabolite, cotinine. For U.S. adult nonsmokers of working age, we estimate median cotinine values of about 1.0 nanogram per milliliter (ng/ml)in plasma, and 6.2 ng/ml in urine; for most-exposed nonsmokers, we estimate cotinine concentrations of about 10 ng/ml in plasma and 62 ng/ml in urine. These values are consistent to within 15% of the cotinine values observed in contemporaneous clinical epidemiological studies. Corresponding median risk from ETS exposure in U.S. nonsmokers during the 1980s is estimated at about two lung cancer deaths (LCDs)per 1000 at risk, and for most-exposed nonsmokers, about two LCDs per 100. Risks abroad appear similar. Modeling of the lung cancer mortality risk from passive smoking suggests that de minimis [i.e., “acceptable” (10^-6)], risk occurs at an 8-hr time-weighted-average exposure concentration of 7.5 nanograms of ETS nicotine per cubic meter of workplace air for a working lifetime of 40 years. This model is based upon a linear exposure-response relationship validated by physical, clinical, and epidemiological data. From available data, it appears that workplaces without effective smoking policies considerably exceed this de minimis risk standard. For a substantial fraction of the 59 million nonsmoking workers in the U.S., current workplace exposure to ETS also appears to pose risks exceeding the de manifestos risk level above which carcinogens are strictly regulated by the federal government.