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.     

Hexavalent Chromium and Lung Cancer in the Chromate Industry: A Quantitative Risk Assessment

The purpose of this investigation was to estimate excess lifetime risk of lung cancer death resulting from occupational exposure to hexavalent-chromium-containing dusts and mists. The mortality experience in a previously studied cohort of 2,357 chromate chemical production workers with 122 lung cancer deaths was analyzed with Poisson regression methods. Extensive records of air samples evaluated for water-soluble total hexavalent chromium were available for the entire employment history of this cohort. Six different models of exposure-response for hexavalent chromium were evaluated by comparing deviances and inspection of cubic splines. Smoking (pack-years) imputed from cigarette use at hire was included in the model. Lifetime risks of lung cancer death from exposure to hexavalent chromium (assuming up to 45 years of exposure) were estimated using an actuarial calculation that accounts for competing causes of death. A linear relative rate model gave a good and readily interpretable fit to the data. The estimated rate ratio for 1 mg/m3-yr of cumulative exposure to hexavalent chromium (as CrO3), with a lag of five years, was RR=2.44 (95% CI=1.54-3.83). The excess lifetime risk of lung cancer death from exposure to hexavalent chromium at the current OSHA permissible exposure limit (PEL) (0.10 mg/m3) was estimated to be 255 per 1,000 (95% CI: 109-416). This estimate is comparable to previous estimates by U.S. EPA, California EPA, and OSHA using different occupational data. Our analysis predicts that current occupational standards for hexavalent chromium permit a lifetime excess risk of dying of lung cancer that exceeds 1 in 10, which is consistent with previous risk assessments.     

Estimated Cancer Risk Associated with Occupational Asbestos Exposure

This paper estimates the number of workers in the United States who were occupationally exposed to asbestos during and after World War II and assesses the impact of this exposure on overall cancer mortality. The results suggest that over half of the estimated 7–8 million potentially exposed workers employed between 1940 and 1970 may still be alive and at risk of dying from some form of asbestos-related cancer. While the maximum number of excess cancer deaths associated with this occupational exposure is likely to occur sometime in this decade, such deaths will continue to be seen for many years thereafter. At their peak, these deaths may account for an estimated 3% of the annual cancer death toll, with an associated range of 1.4–4.4%.     

An Exposure Assessment of Methyl Mercury via Fish Consumption for the Japanese Population

The objective of this article was to propose an exposure assessment model to describe the relationship between fish consumption and body methyl mercury (MeHg) levels in the Japanese population. Individual MeHg intake was estimated by the summation of species-specific fish consumption multiplied by species-specific fish MeHg levels. The distribution of fish consumed by individuals and the MeHg level in each fish species were assigned based on published data from Japanese government institutions. The probability of MeHg intake for a population was accomplished through a Monte Carlo simulation by the random sampling of fish consumption and species-specific MeHg levels. Internal body MeHg levels in blood and hair were estimated using a one-compartment model. Overall, the mean value of MeHg intake for the Japanese population was estimated to be 6.76 μg/day or 0.14 μg/kg body weight per day (bw/day), while the mean value for the hair mercury level was 2.02 μg/g. Compared with the survey data that tabulated hair mercury levels in a cross-section of the Japanese population, the simulation results matched the hair mercury survey data very well for women, but somewhat underestimated for men and all of the population. This exposure assessment model is a useful attempt at further risk assessment with respect to a risk-benefit analysis.     

Comparative Risks of Cancer from Drywall Finishing Based on Stochastic Modeling of Cumulative Exposures to Respirable Dusts and Chrysotile Asbestos Fibers

Sanding joint compounds is a dusty activity and exposures are not well characterized. Until the mid 1970s, asbestos‐containing joint compounds were used by some people such that sanding could emit dust and asbestos fibers. We estimated the distribution of 8‐h TWA concentrations and cumulative exposures to respirable dusts and chrysotile asbestos fibers for four worker groups: (1) drywall specialists, (2) generalists, (3) tradespersons who are bystanders to drywall finishing, and (4) do‐it‐yourselfers (DIYers). Data collected through a survey of experienced contractors, direct field observations, and literature were used to develop prototypical exposure scenarios for each worker group. To these exposure scenarios, we applied a previously developed semi‐empirical mathematical model that predicts area as well as personal breathing zone respirable dust concentrations. An empirical factor was used to estimate chrysotile fiber concentrations from respirable dust concentrations. On a task basis, we found mean 8‐h TWA concentrations of respirable dust and chrysotile fibers are numerically highest for specialists, followed by generalists, DIYers, and bystander tradespersons; these concentrations are estimated to be in excess of the respective current but not historical Threshold Limit Values. Due to differences in frequency of activities, annual cumulative exposures are highest for specialists, followed by generalists, bystander tradespersons, and DIYers. Cumulative exposure estimates for chrysotile fibers from drywall finishing are expected to result in few, if any, mesothelioma or excess lung cancer deaths according to recently published risk assessments. Given the dustiness of drywall finishing, we recommend diligence in the use of readily available source controls.     

Predicting Future Excess Events in Risk Assessment

Risk characterization in a study population relies on cases of disease or death that are causally related to the exposure under study. The number of such cases, so-called "excess" cases, is not just an indicator of the impact of the risk factor in the study population, but also an important determinant of statistical power for assessing aspects of risk such as age-time trends and susceptible subgroups. In determining how large a population to study and/or how long to follow a study population to accumulate sufficient excess cases, it is necessary to predict future risk. In this study, focusing on models involving excess risk with possible effect modification, we describe a method for predicting the expected magnitude of numbers of excess cases and assess the uncertainty in those predictions. We do this by extending Bayesian APC models for rate projection to include exposure-related excess risk with possible effect modification by, e.g., age at exposure and attained age. The method is illustrated using the follow-up study of Japanese Atomic-Bomb Survivors, one of the primary bases for determining long-term health effects of radiation exposure and assessment of risk for radiation protection purposes. Using models selected by a predictive-performance measure obtained on test data reserved for cross-validation, we project excess counts due to radiation exposure and lifetime risk measures (risk of exposure-induced deaths (REID) and loss of life expectancy (LLE)) associated with cancer and noncancer disease deaths in the A-Bomb survivor cohort.     

Risk Assessment for Aflatoxin: II. Implications of Human Epidemiology Data

A review of epidemiology literature revealed that only studies conducted in Africa and Asia included data adequate to permit quantitative assessment of the dose-response relationship between aflatoxin exposure levels and liver cancer rates. Although these studies were judged adequate, their direct use to predict risks in U.S. populations may be questioned since hepatitis B virus (HBV) infections are far more common in the studied areas than in the U.S. Recent research indicates that, if aflatoxin contributes to the development of liver cancer, it almost always does so in the presence of HBV infection. The African/Asian data do not permit us to estimate the potency of aflatoxin in the absence of HBV. Recognizing this, these data can only be used to establish upper limits for the predicted excess lifetime risk for liver cancer in the U.S. When used in conjunction with aflatoxin exposure estimates for the Southeast U.S., these data predict a liver cancer rate, due to aflatoxin alone, far above that actually observed due to all causes; this provides an indication of the conservatism of this approach. Data from the Southeast U.S. may be used to estimate an excess lifetime risk for liver cancer of 2.17 x 10(-6) x (aflatoxin intake, ng/kg/day).     

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.     

Projections of Cancer Risks Attributable to Future Exposure to Asbestos

To assess the maximum possible impact of further government regulation of asbestos exposure, projections were made of the use of asbestos in nine product categories for the years 1985-2000. A life table risk assessment model was then developed to estimate the excess cases of cancer and lost person-years of life likely to occur among those occupationally and nonoccupationally exposed to the nine asbestos product categories manufactured in 1985-2000. These estimates were made under the assumption that government regulation remains at its 1985 level. Use of asbestos in the nine product categories was predicted to decline in all cases except for friction products. The risk assessment results show that, although the cancer risks from future exposure to asbestos are significantly less than those from past exposures, in the absence of more stringent regulations, a health risk remains.     

An Analysis of the Uncertainties in Estimates of Radon-Induced Lung Cancer

A recent report by the National Academy of Sciences estimates that the radiation dose to the bronchial epithelium, per working level month (WLM) of radon daughter exposure, is about 30% lower for residential exposures than for exposures received in underground mines. Adjusting the previously published BEIR IV radon risk model accordingly, the unit risk for indoor exposures of the general population is about 2.2 x 10(-4) lung cancer deaths (lcd)/WLM. Using results from EPA's National Residential Radon Survey, the average radon level is estimated to be about 1.25 pCi/L, and the annual average exposure about 0.242 WLM. Based on these estimates, 13,600 radon-induced lcd/yr are projected for the United States. A quantitative uncertainty analysis was performed, which considers: statistical uncertainties in the epidemiological studies of radon-exposed miners; the dependence of risk on age at, and time since, exposure; the extrapolation of risk estimates from mines to homes based on comparative dosimetry; and uncertainties in the radon daughter levels in homes and in the average residential occupancy. Based on this assessment of the uncertainties in the unit risk and exposure estimates, an uncertainty range of 7000-30000 lcd/yr is derived.     

Review of Radon and Lung Cancer Risk

Radon, a long-established cause of lung cancer in uranium and other underground miners, has recently emerged as a potentially important cause of lung cancer in the general population. The evidence for widespread exposure of the population to radon and the well-documented excess of lung cancer among underground miners exposed to radon decay products have raised concern that exposure to radon progeny might also be a cause of lung cancer in the general population. To date, epidemiological data on the lung cancer risk associated with environmental exposure to radon have been limited. Consequently, the lung cancer hazard posed by radon exposure in indoor air has been addressed primarily through risk estimation procedures. The quantitative risks of lung cancer have been estimated using exposure-response relations derived from the epidemiological investigations of uranium and other underground miners. We review five of the more informative studies of miners and recent risk projection models for excess lung cancer associated with radon. The principal models differ substantially in their underlying assumptions and consequently in the resulting risk projections. The resulting diversity illustrates the substantial uncertainty that remains concerning the most appropriate model of the temporal pattern of radon-related lung cancer. Animal experiments, further follow-up of the miner cohorts, and well-designed epidemiological studies of indoor exposure should reduce this uncertainty.     

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).     

A Trichloroethylene Risk Assessment Using a Monte Carlo Analysis of Parameter Uncertainty in Conjunction with Physiologically-Based Pharmacokinetic Modeling

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10^-6 lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10^-6 risk.     

Multi-Stage Model Estimates of Lung Cancer Risk from Exposure to Diesel Exhaust, Based on a U.S. Railroad Worker Cohort

A California Environmental Protection Agency (Cal/EPA) report concluded that a reasonable and likely explanation for the increased lung cancer rates in numerous epidemiological studies is a causal association between diesel exhaust exposure and lung cancer. A version of the present analysis, based on a retrospective study of a U.S. railroad worker cohort, provided the Cal/EPA report with some of its estimates of lung cancer risk associated with diesel exhaust. The individual data for that cohort study furnish information on age, employment, and mortality for 56,000 workers over 22 years. Related studies provide information on exposure concentrations. Other analyses of the original cohort data reported finding no relation between measures of diesel exhaust and lung cancer mortality, while a Health Effects Institute report found the data unsuitable for quantitative risk assessment. None of those three works used multistage models, which this article uses in finding a likely quantitative, positive relations between lung cancer and diesel exhaust. A seven-stage model that has the last or next-to-last stage sensitive to diesel exhaust provides best estimates of increase in annual mortality rate due to each unit of concentration, for bracketing assumptions on exposure. Using relative increases of risk and multiplying by the background lung cancer mortality rates for California, the 95% upper confidence limit of the 70-year unit risks for lung cancer is estimated to be in the range 2.1 x 10(-4) (microg/m3)(-1) to 5.5 x 10(-4) (microg/m3)(-1). These risks constitute the low end of those in the Cal/EPA report and are below those reported by previous investigators whose estimates were positive using human data.     

Health Risk Assessment After Decontamination of the Beaches Polluted by the Wrecked ERIKA Tanker

Following the wreck of the oil tanker ERIKA off the north-west coast of France in December 1999, cleaning up of the beaches involved considerable work, which in any case could not be perfect. This raised the question of the short- and long-term health risks for the future bathers related to the toxicity of the remaining oil polycyclic aromatic hydrocarbons (PAHs). This risk assessment study was conducted to help health authorities plan risk management policies and inform the public. Thirty-six beaches were selected, representing a sample of the most frequently encountered topographic and beach usage situations; seven "control" beaches, unspoiled by ERIKA, were also investigated. Samples of water and sand were taken from each site, as well as from the surface of rocks. The 16 PAHs selected by the U.S. EPA were quantified in each environment. Several scenarios of exposure were contemplated: (1) a child between 2 and 4 years accidentally ingesting a small ball of fuel, (2) a child daily exposed throughout his holiday-time stay, (3) an adult (including a pregnant woman) spending his/her holidays on the coast, (4) an adult working on the beach, (5) and an adult practicing water sports. Among the available and significant toxicological values, the most conservative ones were selected for computing risks. The sand and water, after decontamination, were slightly polluted (respectively, 7.8 microg/kg and 23.3 ng/l of total 16 PAHs), with values similar to those found in the control beaches. By contrast, the rocky areas in some places were still highly polluted (up to 23 mg/kg on the surface layer). No lethal risk was found for a young child who had accidentally ingested a small ball of fuel. The life-long excess risks for skin cancer and for all other cancers were about 10-5 in scenarios including contact with the polluted rocks. In all other cases, excess risks were considerably lower. The hazard quotient for teratogenic effects was very small, except in scenarios where pregnant women would walk among rocks containing high pollution levels. In conclusion, exposure was mainly associated with polluted water among children, and with spoiled rocks for adults. Despite uncertainties, mainly dealing with the prediction of long-term risks following a short-term exposure, this study showed that beaches where pollution was no longer visible after decontamination did not entail any significant health risks and could be opened to the public.     

Foodborne Exposure to Pesticides and Methylmercury in the United Arab Emirates

As part of a comprehensive environmental health strategic planning project initiated by the government of Abu Dhabi, we assessed potential dietary exposure in the United Arab Emirates (UAE) to methylmercury (in seafood) and pesticides (in fruits and vegetables) above international guideline levels. We present results for the UAE population by age, gender, and body mass index. Our results show very low daily risks of exposure to pesticides in fruits and vegetables at levels exceeding WHO guidelines even under the conservative assumption that no pesticides are removed during washing and food preparation. Thus, exposure to pesticides on fruits and vegetables does not appear to be a major public health concern in the UAE. The chances of exposure to methylmercury in seafood are much higher; our model estimates a mean 1 in 5 daily risk of exceeding the FAO/WHO provisional tolerable weekly intake. However, great caution should be used in interpreting these results, as we analyzed only the risks and not the substantial benefits of fish consumption. In fact, previous studies have demonstrated that exposure to the n‐3 polyunsaturated fatty acids in fish can increase IQ in developing children, and it can substantially decrease the risk in adults of coronary heart disease and stroke. Further research is warranted to compare the risk of Me‐Hg exposure from fish to the nutritional benefits of fish consumption in the UAE and to determine appropriate methods to communicate risk and benefit information to the UAE population.     

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.     

Consumption of Bovine Spongiform Encephalopathy (BSE) Contaminated Beef and the Risk of Variant Creutzfeldt‐Jakob Disease

To date, the variant Creutzfeldt‐Jakob disease (vCJD) risk assessments that have been performed have primarily focused on predicting future vCJD cases in the United Kingdom, which underwent a bovine spongiform encephalopathy (BSE) epidemic between 1980 and 1996. Surveillance of potential BSE cases was also used to assess vCJD risk, especially in other BSE‐prevalent EU countries. However, little is known about the vCJD risk for uninfected individuals who accidentally consume BSE‐contaminated meat products in or imported from a country with prevalent BSE. In this article, taking into account the biological mechanism of abnormal prion PrP^res aggregation in the brain, the probability of exposure, and the expected amount of ingested infectivity, we establish a stochastic mean exponential growth model of lifetime exposure through dietary intake. Given the findings that BSE agents behave similarly in humans and macaques, we obtained parameter estimates from experimental macaque data. We then estimated the accumulation of abnormal prions to assess lifetime risk of developing clinical signs of vCJD. Based on the observed number of vCJD cases and the estimated number of exposed individuals during the BSE epidemic period from 1980 to 1996 in the United Kingdom, an exposure threshold hypothesis is proposed. Given the age‐specific risk of infection, the hypothesis explains the observations very well from an extreme‐value distribution fitting of the estimated BSE infectivity exposure. The current BSE statistics in the United Kingdom are provided as an example.     

A dose-response analysis of skin cancer from inorganic arsenic in drinking water

A study of the prevalence of skin cancer among 40,421 persons consuming arsenic-contaminated drinking water in Taiwan was used for a cancer dose-response assessment of ingested arsenic. The numbers of persons at risk over three dose intervals and four exposure durations were estimated from the data in order to apply the method of maximum likelihood to a multistage-Weibull time/dose-response model. A constant exposure level since birth for each of the exposure categories was assumed. It was found that the cumulative hazard increases as a power of three in age, and is linear or quadratic (with a linear coefficient) in dose. Observations from a smaller epidemiologic survey in Mexico were similar to what would be predicted from the model of the Taiwan data. Assuming that the skin cancer risk from ingested arsenic in the American population would also be similar to the Taiwan population, an American male would have a lifetime risk of developing skin cancer of 1.3 x 10(-3) (3.0 x 10(-3] if exposed to 1 microgram/kg/day for a 76-year lifespan (median lifespan in the U.S.).