Cancer Risk Estimation for Mixtures of Coal Tars

Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 × 10⁻⁴ (ppm coal tar in total diet) + 240 × 10⁻⁴ (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 × 10⁻⁴ (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 × 10⁻³ per μg per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 × 10⁻³ per μg per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.     

Mlonte Carlo Techniques for Quantitative Uncertainty Analysis in Public Health Risk Assessments

Most public health risk assessments assume and combine a series of average, conservative, and worst-case values to derive a conservative point estimate of risk. This procedure has major limitations. This paper demonstrates a new methodology for extended uncertainty analyses in public health risk assessments using Monte Carlo techniques. The extended method begins as do some conventional methods--with the preparation of a spreadsheet to estimate exposure and risk. This method, however, continues by modeling key inputs as random variables described by probability density functions (PDFs). Overall, the technique provides a quantitative way to estimate the probability distributions for exposure and health risks within the validity of the model used. As an example, this paper presents a simplified case study for children playing in soils contaminated with benzene and benzo(a)pyrene (BaP).     

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.).     

Comparative Potency Method for Cancer Risk Assessment: Application to Diesel Particulate Emissions1

An estimation of the human lung cancer “unit risk” from diesel engine particulate emissions has been made using a comparative potency approach. This approach involves evaluating the tumorigenic and mutagenic potencies of the particulates from four diesel and one gasoline engine in relation to other combustion and pyrolysis products (coke oven, roofing tar, and cigarette smoke) that cause lung cancer in humans. The unit cancer risk is predicated on the linear nonthreshold extrapolation model and is the individual lifetime excess lung cancer risk from continuous exposure to 1 μg carcinogen per m³ inhaled air. The human lung cancer unit risks obtained from the epidemiologic data for coke oven workers, roofing tar applicators, and cigarette smokers were, respectively, 9.3 × 10^?4, 3.6 × 10^?4, and 2.2 × 10^?6 per μg particulate organics per m³ air. The comparative potencies of these three materials and the diesel and gasoline engine exhaust particulates (as organic extracts) were evaluated by in vivo tumorigenicity bioassays involving skin initiation and skin carcinogenicity in SENCAR mice and by the in vitro bioassays that proved suitable for this analysis: Ames Salmonella microsome bioassay, L5178Y mouse lymphoma cell mutagenesis bioassay, and sister chromatid exchange bioassay in Chinese hamster ovary cells. The relative potencies of the coke oven, roofing tar, and cigarette smoke emissions, as determined by the mouse skin initiation assay, were within a factor of 2 of those determined using the epidemiologic data. The relative potencies, from the in vitro bioassays as compared to the human data, were similar for coke oven and roofing tar, but for the cigarette smoke condensate the in vitro tests predicted a higher relative potency. The mouse skin initiation bioassay was used to determine the unit lung cancer risk for the most potent of the diesel emissions. Based on comparisons with coke oven, roofing tar, and cigarette smoke, the unit cancer risk averaged 4.4 × 10^?4. The unit lung cancer risks for the other, less potent motor-vehicle emissions were determined from their comparative potencies relative to the most potent diesel using three in vitro bioassays. There was a high correlation between the in vitro and in vivo bioassays in their responses to the engine exhaust particulate extracts. The unit lung cancer risk per μg particulates per m³ for the automotive diesel and gasoline exhaust particulates ranged from 0.20 × 10^?4 to 0.60 × 10^?4; that for the heavy-duty diesel engine was 0.02 × 10^?4. These unit risks provide the basis for a future assessment of human lung cancer risks when combined with human population exposure to automotive emissions.     

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.     

Comparison of the Cancer Risk of Methylene Chloride Predicted from Animal Bioassay Data with the Epidemiologic Evidence

Methylene chloride has been shown to be a lung and liver carcinogen in the mouse; yet, the current epidemiologic data show no adverse health effects associated with chronic exposure to this compound. Hearne et al. have compared the results of a large mortality study on occupational exposure to methylene chloride to the human risk predictions based on the rodent bioassay to point out the inconsistency between the animal toxicologic and human epidemiologic data. The maximum number of lung and liver cancers predicted due to methylene chloride exposure based on the rodent bioassay data was 24 compared to 14 deaths from these cancers actually observed in the Hearne et al. epidemiology study. We assess the minimum risk detectable by the human study in order to calculate the upperbound potency of methylene chloride and compare it to the potency derived from the bioassay data. Results from the epidemiology study imply an upperbound potency of 1.5 x 10(-2) per ppm, compared to 1.4 x 10(-2) per ppm calculated using the most conservative analysis of the animal data. We conclude that the negative epidemiology study of Hearne et al. is not sufficiently powerful to show that the risk is inconsistent with the human risk estimated by modeling the rodent bioassay data. Specifically, the doses to which the workers were exposed, the population studied, and the latency period were not adequate to determine that the risks are outside the bounds of the risk estimates predicted by low-dose modeling of the animal data.     

An Interagency Comparison of Screening-Level Risk Assessment Approaches

Approaches to risk assessment have been shown to vary among regulatory agencies and across jurisdictional boundaries according to the different assumptions and justifications used. Approaches to screening-level risk assessment from six international agencies were applied to an urban case study focusing on benzo[a]pyrene (B[a]P) exposure and compared in order to provide insight into the differences between agency methods, assumptions, and justifications. Exposure estimates ranged four-fold, with most of the dose stemming from exposure to animal products (8-73%) and plant products (24-88%). Total cancer risk across agencies varied by two orders of magnitude, with exposure to air and plant and animal products contributing most to total cancer risk, while the air contribution showed the greatest variability (1-99%). Variability in cancer risk of 100-fold was attributed to choices of toxicological reference values (TRVs), either based on a combination of epidemiological and animal data, or on animal data. The contribution and importance of the urban exposure pathway for cancer risk varied according to the TRV and, ultimately, according to differences in risk assessment assumptions and guidance. While all agency risk assessment methods are predicated on science, the study results suggest that the largest impact on the differential assessment of risk by international agencies comes from policy and judgment, rather than science.     

Uncertainty and Variability in Human Exposures to Soil Contaminants Through Home-Grown Food: A Monte Carlo Assessment

This paper presents a general model for exposure to homegrown foods that is used with a Monte Carlo analysis to determine the relative contributions of variability (Type A uncertainty) and true uncertainty (Type B uncertainty) to the overall variance in prediction of the dose-to-concentration ratio. Although classification of exposure inputs as uncertain or variable is somewhat subjective, food consumption rates and exposure duration are judged to have a predicted variance that is dominated by variability among individuals by age, income, culture, and geographical region. Whereas, biotransfer factors and partition factors are inputs that, to a large extent, involve uncertainty. Using ingestion of fruits, vegetables, grains, dairy products, and meat and soils assumed to be contaminated by hexachlorbenzene (HCB) and benzo(a)pyrene (BaP) as cases studies, a Monte Carlo analysis is used to explore the relative contribution of uncertainty and variability to overall variance in the estimated distribution of potential dose within the population that consumes homegrown foods. It is found that, when soil concentrations are specified, variances in ratios of dose-to-concentration for HCB are equally attributable to uncertainty and variability, whereas for BaP, variance in these ratios is dominated by true uncertainty.     

Intake Fraction Variability Between Air Pollution Emission Sources Inside an Urban Area

The cost‐effective mitigation of adverse health effects caused by air pollution requires information on the contribution of different emission sources to exposure. In urban areas the exposure potential of different sources may vary significantly depending on emission height, population density, and other factors. In this study, we quantified this intraurban variability by predicting intake fraction (iF) for 3,066 emission sources in Warsaw, Poland. iF describes the fraction of the pollutant that is inhaled by people in the study area. We considered the following seven pollutants: particulate matter (PM), nitrogen oxides (NO_x), sulfur dioxide (SO₂), benzo[a] pyrene (BaP), nickel (Ni), cadmium (Cd), and lead (Pb). Emissions for these pollutants were grouped into four emission source categories (Mobile, Area, High Point, and Other Point sources). The dispersion of the pollutants was predicted with the CALPUFF dispersion model using the year 2005 emission rate data and meteorological records. The resulting annual average concentrations were combined with population data to predict the contribution of each individual source to population exposure. The iFs for different pollutant‐source category combinations varied between 51 per million (PM from Mobile sources) and 0.013 per million (sulfate PM from High Point sources). The intraurban iF variability for Mobile sources primary PM emission was from 4 per million to 100 per million with the emission‐weighted iF of 44 per million. These results propose that exposure due to intraurban air pollution emissions could be decreased more effectively by specifically targeting sources with high exposure potency rather than all sources.     

Stochastic Estimates of Exposure and Cancer Risk from Carbon Tetrachloride Released to the Air from the Rocky Flats Plant

Carbon tetrachloride is a degreasing agent that was used at the Rocky Flats Plant (RFP) in Colorado to clean product components and equipment. The chemical is considered a volatile organic compound and a probable human carcinogen. During the time the plant operated (1953-1989), most of the carbon tetrachloride was released to the atmosphere through building exhaust ducts. A smaller amount was released to the air via evaporation from open-air burn pits and ground-surface discharge points. Airborne releases from the plant were conservatively estimated to be equivalent to the amount of carbon tetrachloride consumed annually by the plant, which was estimated to be between 3.6 and 180 Mg per year. This assumption was supported by calculations that showed that most of the carbon tetrachloride discharged to the ground surface would subsequently be released to the atmosphere. Atmospheric transport of carbon tetrachloride from the plant to the surrounding community was estimated using a Gaussian Puff dispersion model (RATCHET). Time-integrated concentrations were estimated for nine hypothetical but realistic exposure scenarios that considered variation in lifestyle, location, age, and gender. Uncertainty distributions were developed for cancer slope factors and atmospheric dispersion factors. These uncertainties were propagated through to the final risk estimate using Monte Carlo techniques. The geometric mean risk estimates varied from 5.2 x 10(-6) for a hypothetical rancher or laborer working near the RFP to 3.4 x 10(-9) for an infant scenario. The distribution of incremental lifetime cancer incidence risk for the hypothetical rancher was between 1.3 x 10(-6) (5% value) and 2.1 x 10(-5) (95% value). These estimates are similar to or exceed estimated cancer risks posed by releases of radionuclides from the site.     

Benchmark Dose Risk Assessment for Formaldehyde Using Airflow Modeling and a Single-Compartment, DNA-Protein Cross-Link Dosimetry Model to Estimate Human Equivalent Doses

Formaldehyde induced squamous-cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose-response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low-dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde-induced DNA-protein cross-links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose-response relationship for cell proliferation at low exposure levels, the dose-response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.     

Estimating Preventable Fractions of Disease Caused by a Specified Biological Mechanism: PAHs in Smoking Lung Cancers as an Example

Epidemiology textbooks often interpret population attributable fractions based on 2 x 2 tables or logistic regression models of exposure-response associations as preventable fractions, i.e., as fractions of illnesses in a population that would be prevented if exposure were removed. In general, this causal interpretation is not correct, since statistical association need not indicate causation; moreover, it does not identify how much risk would be prevented by removing specific constituents of complex exposures. This article introduces and illustrates an approach to calculating useful bounds on preventable fractions, having valid causal interpretations, from the types of partial but useful molecular epidemiological and biological information often available in practice. The method applies probabilistic risk assessment concepts from systems reliability analysis, together with bounding constraints for the relationship between event probabilities and causation (such as that the probability that exposure X causes response Y cannot exceed the probability that exposure X precedes response Y, or the probability that both X and Y occur) to bound the contribution to causation from specific causal pathways. We illustrate the approach by estimating an upper bound on the contribution to lung cancer risk made by a specific, much-discussed causal pathway that links smoking to a polycyclic aromatic hydrocarbon (PAH) (specifically, benzo(a)pyrene diol epoxide-DNA) adducts at hot spot codons at p53 in lung cells. The result is a surprisingly small preventable fraction (of perhaps 7% or less) for this pathway, suggesting that it will be important to consider other mechanisms and non-PAH constituents of tobacco smoke in designing less risky tobacco-based products.     

Addressing Nonlinearity in the Exposure-Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

Ethylene oxide (EO) has been identified as a carcinogen in laboratory animals. Although the precise mechanism of action is not known, tumors in animals exposed to EO are presumed to result from its genotoxicity. The overall weight of evidence for carcinogenicity from a large body of epidemiological data in the published literature remains limited. There is some evidence for an association between EO exposure and lympho/hematopoietic cancer mortality. Of these cancers, the evidence provided by two large cohorts with the longest follow-up is most consistent for leukemia. Together with what is known about human leukemia and EO at the molecular level, there is a body of evidence that supports a plausible mode of action for EO as a potential leukemogen. Based on a consideration of the mode of action, the events leading from EO exposure to the development of leukemia (and therefore risk) are expected to be proportional to the square of the dose. In support of this hypothesis, a quadratic dose-response model provided the best overall fit to the epidemiology data in the range of observation. Cancer dose-response assessments based on human and animal data are presented using three different assumptions for extrapolating to low doses: (1) risk is linearly proportionate to dose; (2) there is no appreciable risk at low doses (margin-of-exposure or reference dose approach); and (3) risk below the point of departure continues to be proportionate to the square of the dose. The weight of evidence for EO supports the use of a nonlinear assessment. Therefore, exposures to concentrations below 37 microg/m3 are not likely to pose an appreciable risk of leukemia in human populations. However, if quantitative estimates of risk at low doses are desired and the mode of action for EO is considered, these risks are best quantified using the quadratic estimates of cancer potency, which are approximately 3.2- to 32-fold lower, using alternative points of departure, than the linear estimates of cancer potency for EO. An approach is described for linking the selection of an appropriate point of departure to the confidence in the proposed mode of action. Despite high confidence in the proposed mode of action, a small linear component for the dose-response relationship at low concentrations cannot be ruled out conclusively. Accordingly, a unit risk value of 4.5 x 10(-8) (microg/m3)(-1) was derived for EO, with a range of unit risk values of 1.4 x 10(-8) to 1.4 x 10(-7) (microg/m3)(-1) reflecting the uncertainty associated with a theoretical linear term at low concentrations.     

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.     

Radiocesium in Fish from the Savannah River and Steel Creek: Potential Food Chain Exposure to the Public

This study examined radiocesium (137Cs) levels in fish from the vicinity of the Department of Energy's Savannah River Site (SRS), a former nuclear weapons production facility in South Carolina. Fish from the Savannah River were sampled above (upstream), along, and below (downstream) the SRS, and from Steel Creek, a tributary that runs through the SRS. There was some off-site contamination of 137Cs in the Savannah River watershed due to low-level releases from past nuclear production on the SRS. The null hypotheses tested were that there would be no differences in 137Cs levels as a function of location along the river, and between species collected from the river and from Steel Creek on the SRS. For six of eight species of fish collected from the Savannah River, there were no differences in 137Cs levels in muscle from fish collected above, along, or below the SRS; exceptions were bowfin and shellcracker. Fish collected from Steel Creek had significantly higher levels (by about an order of magnitude) of 137Cs in muscle tissue than fish collected in the Savannah River. However, no fish from either Steel Creek or the Savannah River had 137Cs levels above the European Economic Community limit for fresh meat of 0.6 Bq/g. Lifetime cancer risk was calculated using the cancer slope factor of 3.2 x 10(-11)/pCi, and various fish consumption scenarios reflecting actual data from Savannah River fishermen. Using mean 137Cs concentrations and median fish consumption for 70 years for Black males-the group with the highest consumption-the excess lifetime risk associated with the eight species of fish in the Savannah River ranged from 9.0 x 10(-7) to 1.0 x 10(-5). The same calculation for fish from Steel Creek gave risk estimates from 1.4 to 8.0 x 10(-5). The 95% level for consumption by Blacks, however, was about 70 kg/year. Black fishermen consuming that amount of bass from Steel Creek would sustain a lifetime risk of 3.1 x 10(-4), whereas the same consumption of Savannah River bass would yield a risk estimate of 1.5 x 10(-5).     

Risk Assessment of Listeriosis Linked to the Consumption of Two Soft Cheeses Made from Raw Milk: Camembert of Normandy and Brie of Meaux

This article reports a quantitative risk assessment of human listeriosis linked to the consumption of soft cheeses made from raw milk. Risk assessment was based on data purposefully acquired inclusively over the period 2000-2001 for two French cheeses, namely: Camembert of Normandy and Brie of Meaux. Estimated Listeria monocytogenes concentration in raw milk was on average 0.8 and 0.3 cells/L, respectively, in Normandy and Brie regions. A Monte Carlo simulation was used to account for the time-temperature history of the milk and cheeses from farm to table. It was assumed that cell progeny did not spread within the solid cheese matrix (as they would be free to do in liquid broth). Interaction between pH and temperature was accounted for in the growth model. The simulated proportion of servings with no L. monocytogenes cell was 88% for Brie and 82% for Camembert. The 99th percentile of L. monocytogenes cell numbers in servings of 27 g of cheese was 131 for Brie and 77 for Camembert at the time of consumption, corresponding respectively to three and five cells of L. monocytogenes per gram. The expected number of severe listeriosis cases would be < or =10(-3) and < or =2.5 x 10(-3) per year for 17 million servings of Brie of Meaux and 480 million servings of Camembert of Normandy, respectively.     

Estimates of Lifetime-Absorbed Daily Doses from the Use of Personal-Care Products Containing Polyacrylamide: A Monte Carlo Analysis

Estimates of the lifetime-absorbed daily dose (LADD) of acrylamide resulting from use of representative personal-care products containing polyacrylamides have been developed. All of the parameters that determine the amount of acrylamide absorbed by an individual vary from one individual to another. Moreover, for some parameters there is uncertainty as to which is the correct or representative value from a range of values. Consequently, the parameters used in the estimation of the LADD of acrylamide from usage of a particular product type (e.g., deodorant, makeup, etc.) were represented by distributions evaluated using Monte Carlo analyses.((1-4)) From these data, distributions of values for key parameters, such as the amount of acrylamide in polyacrylamide, absorption fraction, etc., were defined and used to provide a distribution of LADDs for each personal-care product. The estimated total acrylamide LADD (across all products) for males and females at the median, mean, and 95th percentile of the distribution of individual LADD values were 4.7 x 10(-8), 2.3 x 10(-7), and 7.3 x 10(-7) mg/kg/day for females and 3.6 x 10(-8), 1.7 x 10(-7), and 5.4 x 10(-7) mg/kg/day for males. The ratio of the LADDs to risk-specific dose corresponding to a target risk level of 1 x 10(-5), the acceptable risk level for this investigation, derived using approaches typically used by the FDA, the USEPA, and proposed for use by the European Union (EU) were also calculated. All ratios were well below 1, indicating that all the extra lifetime cancer risk from the use of polyacrylamide-containing personal-care products, in the manner assumed in this assessment, are well below acceptable levels. Even if it were assumed that an individual used all of the products together, the estimated LADD would still provide a dose that was well below the acceptable risk levels.     

Compressed Natural Gas Bus Safety: A Quantitative Risk Assessment

This study assesses the fire safety risks associated with compressed natural gas (CNG) vehicle systems, comprising primarily a typical school bus and supporting fuel infrastructure. The study determines the sensitivity of the results to variations in component failure rates and consequences of fire events. The components and subsystems that contribute most to fire safety risk are determined. Finally, the results are compared to fire risks of the present generation of diesel-fueled school buses. Direct computation of the safety risks associated with diesel-powered vehicles is possible because these are mature technologies for which historical performance data are available. Because of limited experience, fatal accident data for CNG bus fleets are minimal. Therefore, this study uses the probabilistic risk assessment (PRA) approach to model and predict fire safety risk of CNG buses. Generic failure data, engineering judgments, and assumptions are used in this study. This study predicts the mean fire fatality risk for typical CNG buses as approximately 0.23 fatalities per 100-million miles for all people involved, including bus passengers. The study estimates mean values of 0.16 fatalities per 100-million miles for bus passengers only. Based on historical data, diesel school bus mean fire fatality risk is 0.091 and 0.0007 per 100-million miles for all people and bus passengers, respectively. One can therefore conclude that CNG buses are more prone to fire fatality risk by 2.5 times that of diesel buses, with the bus passengers being more at risk by over two orders of magnitude. The study estimates a mean fire risk frequency of 2.2 x 10(-5) fatalities/bus per year. The 5% and 95% uncertainty bounds are 9.1 x 10(-6) and 4.0 x 10(-5), respectively. The risk result was found to be affected most by failure rates of pressure relief valves, CNG cylinders, and fuel piping.     

Use of a Chemical Probe to Increase Safety for Human Volunteers in Toxicokinetic Studies

To avoid interspecies extrapolation in toxicokinetics and drug development, it is convenient to directly develop human data. In that case, exposure dose should pose null or negligible risk to the exposed individual, but still be sufficiently high to allow quantification. We propose to reduce the dose received by human volunteers during exposure, and to compensate for loss of information by exposing the same volunteers to a nontoxic agent. This method was applied to develop 1,3-butadiene (BD) exposure protocols for humans. To study the potential of such a procedure, we worked with simulated data. Three exposure times (20, 10, and 5 minutes) and four exposure concentrations (2, 1, 0.8, and 0.5 ppm) were used to define 12 inhalation exposure scenarios for BD. Isoflurane was used as a probe, with simulated exposure of 20 subjects to 20 ppm isoflurane during 15 minutes. Isoflurane or BD-exhaled air concentrations were supposed to be measured 10 times. A three-compartment physiological toxicokinetic model was used to jointly describe BD and isoflurane data. For each subject, BD data were analyzed, in a Bayesian framework, either alone or together with the isoflurane data. The precision of BD metabolic rate constant or fraction metabolized was increased, and bias reduced, when BD and probe data were considered jointly. An exposure to 10 ppm x min BD and 300 ppm x min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm x min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe.