Exposures from chrysotile-containing joint compound: evaluation of new model relating respirable dust to fiber concentrations.

The potential for fiber exposure during historical use of chrysotile-containing joint compounds (JCC) has been documented, but the published data are of limited use for reconstructing exposures and assessing worker risk. Consequently, fiber concentration distributions for workers sanding JCC were independently derived by applying a recently developed model based on published dust measurements from sanding modern-day (asbestos-free) joint compound and compared to fiber concentration distributions based on limited historical measurements. This new procedure relies on factors that account for (i) differences in emission rates between modern-day and JCC and (ii) the number of fibers (quantified by phase contrast microscopy [PCM]) per mass of dust generated by sanding JCC, as determined in a bench-scale chamber study using a recreated JCC, that convert respirable dust concentrations to fiber concentrations. Airborne respirable PCM-fiber concentration medians (and 95% confidence intervals) derived for output variables using the new procedure were 0.26 (0.039, 1.7) f/cm(3) and 0.078 (0.013, 0.47) f/cm(3) , and corresponding total fiber concentrations were 1.2 (0.17, 9.2) f/cm(3) and 0.37 (0.056, 2.5) f/cm(3) , in enclosed and nonenclosed environments, respectively. Corresponding estimates of respirable and total PCM fiber concentrations measured historically during sanding of asbestos-containing joint compound-adjusted for differences between peak and time-weighted average (TWA) concentrations and documented analytical preparation and sampling artifacts-were 0.15 (0.019, 0.95) f/cm(3) and 0.86 (0.11, 5.4) f/cm(3) , respectively. The PCM-fiber concentration distributions estimated using the new procedure bound the distribution estimated from adjusted TWA historical fiber measurements, suggesting reasonable consistency of these estimates taking into account uncertainties addressed in this study.

Potential artifacts associated with historical preparation of joint compound samples and reported airborne asbestos concentrations.

Airborne samples collected in the 1970s for drywall workers using asbestos-containing joint compounds were likely prepared and analyzed according to National Institute of Occupational Safety and Health Method P&CAM 239, the historical precursor to current Method 7400. Experimentation with a re-created, chrysotile-containing, carbonate-based joint compound suggested that analysis following sample preparation by the historical vs. current method produces different fiber counts, likely because of an interaction between the different clearing and mounting chemicals used and the carbonate-based joint compound matrix. Differences were also observed during analysis using Method 7402, depending on whether acetic acid/dimethylformamide or acetone was used during preparation to collapse the filter. Specifically, air samples of sanded chrysotile-containing joint compound prepared by the historical method yielded fiber counts significantly greater (average of 1.7-fold, 95% confidence interval: 1.5- to 2.0-fold) than those obtained by the current method. In addition, air samples prepared by Method 7402 using acetic acid/dimethylformamide yielded fiber counts that were greater (2.8-fold, 95% confidence interval: 2.5- to 3.2-fold) than those prepared by this method using acetone. These results indicated (1) there is an interaction between Method P&CAM 239 preparation chemicals and the carbonate-based joint compound matrix that reveals fibers that were previously bound in the matrix, and (2) the same appeared to be true for Method 7402 preparation chemicals acetic acid/dimethylformamide. This difference in fiber counts is the opposite of what has been reported historically for samples of relatively pure chrysotile dusts prepared using the same chemicals. This preparation artifact should be considered when interpreting historical air samples for drywall workers prepared by Method P&CAM 239.

Impact of spatiotemporal fluctuations in airborne chemical concentration on toxic hazard assessment.

Models widely used to assess atmospheric chemical-dispersion hazards for emergency response rely on acute exposure guideline level (AEGL) or similar concentration guidelines to map geographic areas potentially affected by corresponding levels of toxic severity. By ignoring substantial, random variability in concentration over time and space, such standard methods routinely underestimate the size of potentially affected areas. Underestimation due to temporal fluctuation - applicable to chemicals like hydrogen cyanide (HCN) for which peak concentrations best predict acute toxicity - becomes magnified by spatial fluctuation, defined as heterogeneity in average concentration at each location relative to standard-method predictions. The combined impact of spatiotemporal fluctuation on size of assessed threat areas was studied using a statistical-simulation assessment method calibrated to Joint Urban 2003 Oklahoma City field-tracer data. For a hypothetical 60-min urban release scenario involving HCN gas, the stochastic method predicted that lethal/severe effects could occur in an area 18 or 25 times larger than was predicted by standard methods targeted to a 60-min AEGL, assuming wind speeds > or =2.0 or < or =1.5m/s, respectively. The underestimation doubled when the standard method was targeted to a 10-min AEGL. Further research and field data are needed for improved stochastic methods to assess spatiotemporal fluctuation effects.

Highly elevated PSA and dietary PhIP intake in a prospective clinic-based study among African Americans.

African-American men die from prostate cancer (PC) nearly twice as often as white US men and consume about twice as much of the predominant US dietary heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a genotoxic rat-prostate carcinogen found primarily in well-cooked chicken and beef. To investigate the hypothesis that PhIP exposure increases PC risk, an ongoing prospective clinic-based study compared PC screening outcomes with survey-based estimates of dietary PhIP intake among 40-70-year-old African-American men with no prior PC in Oakland, CA. They completed food-frequency and meat-cooking/consumption questionnaires and had a prostate-specific antigen (PSA) test and digital-rectal exam. Results for 392 men indicated a 17 (+/-17) ng/kg day mean (+/-1 s.d.) daily intake of PhIP, about twice that of white US men of similar age. PhIP intake was attributable mostly to chicken (61%) and positively associated (R(2)=0.32, P<0.0001) with saturated fat intake. An odds ratio (95% confidence interval) of 31 (3.1-690) for highly elevated PSA > or =20 ng/ml was observed in the highest 15% vs lowest 50% of estimated daily PhIP intake (> or =30 vs < or =10 ng/kg day) among men 50+ years old (P=0.0002 for trend) and remained significant after adjustment for self-reported family history of (brother or father) PC, saturated fat intake and total energy intake. PSA measures were higher in African-American men with positive family history (P=0.007 all men, P<0.0001 highest PSA quartile). These preliminary results are consistent with a positive association between PhIP intake and highly elevated PSA, supporting the hypothesis that dietary intervention may help reduce PC risk.

Cell proliferation kinetics and multistage cancer risk models.

Cell-kinetic multistage (CKM) cancer-risk models account for clonal proliferation of postulated intermediate (initiated, premalignant) cell populations during tumorigenesis. To date, almost all CKM models considered have assumed that intermediate, premalignant cells may proliferate exponentially over time in vivo. This "exponential growth" assumption, however, may not always be as biologically plausible as the alternative assumption that cells tend to grow geometrically in time. The general CKM model and applications of it that presume exponential cell growth are reviewed here. Geometric CKM models are then considered, previous erroneous analyses of these models are reviewed, and a corrected mathematical treatment is provided. It is pointed out that the presumption of exponential instead of geometric proliferation kinetics may lead to underestimates of small increments in CKM-predicted cancer risk above background if the geometric assumption is true. An evaluation of pertinent biological evidence is provided, which indicates that precancerous cells may typically proliferate geometrically. Consequently, if CKM models are used for environmental risk assessment, it may be prudent for one to presume geometric cell growth unless specific data support an alternative assumption.

Improved prediction of carcinogenic potencies from mutagenic potencies for chemicals positive in rodents and the Ames test.

Most studies of correlation between logs of mutagenic potency (MP) and cancer potency (CP) have obtained relatively small but statistically significant estimates of correlation (r) and corresponding log-log slope (b, in Log[CP] = a + b Log[MP]). But for mutagenic carcinogens, multistage cancer theory predicts that b and r should be highest when MP values best estimate mutation yields per unit dose at concentrations at least as high as those observed to cause cancer in bioassay animals. To test this hypothesis, the correlation of Ames test and rodent cancer potencies was examined for a total number n of 134 chemicals reported as positive in both assays. Values of maximum significant cancer potency (CP, in [mmol/kg-day]-1) were obtained from a published carcinogenic potency database. Values of maximum mutagenic potency (MP, as revertants per mmol/L-plate) were estimated from 2,347 sets of Ames test data reported by the NTP mutagenicity testing program, supplemented by similar data newly obtained for ten heterocyclic amines. For compounds with one or more significantly positive MP estimates based on approximately linear Ames test dose-response data, linear regression of maximum values of Log(CP) on Log(MP) yielded b = 0.27 +/- 0.065 and r = 0.39 (P = 0.0001, n = 105), similar to previously reported results for relatively large n. As predicted, when MP values were additionally restricted to include only values estimated from Ames test data approximately linear at corresponding lowest-TD50 concentrations, similar regressions yielded significantly improved fits (e.g,. b and r approximately 0.6, P < 10(-7), n = 68). Implications of these findings are discussed concerning the quantitative role that mutations like those measured in the Ames test may have in explaining observed cancer-bioassay results.

Gel microdrop flow cytometry assay for low-dose studies of chemical and radiation cytotoxicity.

Low-level cytotoxicity may affect low-dose dose-response relations for cancer and other endpoints. Conventional colony-forming assays are rarely sensitive enough to examine small changes in cell survival and growth. Automated image-analysis techniques are limited to ca. 10(4) cells/plate. An alternative method involves encapsulation of single proliferating cells into ca. 35-75-microm-diameter agarose gel microdrops (GMDs) that are randomly grouped, differential exposure of these groups, culture at 37 degrees C for 3-5 days, and finally GMD analysis by flow cytometry (FC) to determine the ratio of GMDs containing multiple versus single cells as a measure of clonogenic survival. This GMD/FC assay was used to examine low-dose cell killing induced by a cooked-meat mutagen/rodent-carcinogen (MeIQx) in DNA-repair-deficient/metabolically-sensitive CHO cells. Results of conventional colony-forming assays using up to 30 replicate plates indicate a shouldered, threshold-like dose-response; in contrast, those obtained using the GMD/FC assay suggest "hypersensitivity"-like nonlinearity in dose-response. The GMD/FC assay was also applied to human A549 lung cells after GMD-encapsulation and gamma radiation followed by culture for a total of 4 days, to examine survival after exposure to > or =100 cGy delivered at a relatively low dose rate (0.18 cGy/min). Dose-response for clonogenic growth was again observed to be reduced with apparent nonlinear suggesting hypersensitivity between 0 and 50 cGy, insofar as doses of 5 and 10 cGy appear to be ca. fivefold more effective per unit dose than the 50- or 100-cGy doses used. The GMD/FC assay may thus reveal low-dose dose-response relations for chemical and radiation effects on cell proliferation/killing with implications for low-dose risk assessment.

Reassessment of human peripheral T-lymphocyte lifespan deduced from cytogenetic and cytotoxic effects of radiation.

Estimates of the mean lifetime of human peripheral blood T-lymphocytes (PBTL) have ranged from 1.5 to 10 year. To derive an improved estimate, kinetic and dose parameters of four deterministic, two-compartment models of loss and replacement of human peripheral blood lymphocytes (PBL) were fitted to a previously published extensive data set on loss of dicentrics plus rings (DR) in PBL sampled from X-ray-treated ankylosing spondylitis patients for > 20-year-post-treatment, involving a fixed external-dose regimen (with dose to PBL unknown). The four models investigated all incorporated fixed dose-response submodels for radiation-induced cytogenetic damage and cell killing that were based entirely on in vitro data for X-ray-exposed human PBTL. Two of the models are shown to provide a reasonably good prediction not only of the data on DR loss to which the models were fit, but also of corresponding data on recovery of the mean of measured total PBL. The modelling results indicate that it is unlikely that long-lived human recirculating 'memory' PBTL are homogeneous with respect to lifespan, but rather that two major subpopulations, T1 and T2, are involved having mean lifespans (and approximately 95% confidence limits) estimated to be approximately 1.1 (0.76-1.9) and approximately 6.3 (5.8-6.9) year, respectively. One of the two models consistent with the data posits that T1 (possibly 'short-term antigen-memory') cells are approximately 60% of recirculating T-lymphocytes that convert at a rate of approximately 9% year-1 into T2 (possibly 'long-term antigen-memory') cells, and that the T1 cells are virtually all derived from a central-body source such as thymus and/or central lymphatic tissues.

Estimates of heterocyclic amine intake in the US population.

HA-specific meat concentration estimates using a method that combines laboratory data to predict HA concentrations from meat type, cooking method and meat doneness were used with national dietary data to estimate daily HA intake for segments of the US population. PhIP was found to comprise approximately 70% of US mean dietary intake of total HAs, with pan-frying and chicken being the single cooking method and meat type contributing the greatest to total estimated HA exposures. This analysis demonstrated significantly higher concentrations in grilled/barbecued meats than in other cooked meats. African-American males were estimated to consume nearly twofold and approximately 35 to 40% more PhIP (and total HAs) than white males at ages <16 and >30 years, respectively.

Applicability of alternative models of revertant variance to Ames-test data for 121 mutagenic carcinogens.

Models of sampling variance in replicate revertant scores play a role in analyses of Ames-test data on mutagenicity in Salmonella, both in modeling the dose-response relation and in estimating initial dose-response slope or 'potency', e.g., for use in correlating mutagenic and carcinogenic potencies among different chemicals. Both generalized Poisson (GP) and negative binomial (NB) models of revertant variance have been applied in this way, but their empirical applicability has only been assessed using Ames-test data on a few chemicals. The applicability of these and related variance models was therefore assessed for 1905 such data sets pertaining to 121 putatively mutagenic carcinogens. Only approximately 50% of the data sets analyzed were found to involve a significantly positively correlated dose-response, and < 50% were found to exhibit a plausibly heterogeneous response variance regardless of dose-response correlation. Among data sets with plausibly heterogeneous variance, < 60% were found to exhibit significantly extra-Poisson variability. Among the significantly extra-Poisson data sets, most (> 75% among dose-response correlated data sets) were found to exhibit revertant variance consistent with both the GP and NB models; while the GP model was found to be somewhat more consistent with these data, the NB model more often gave a nominally better fit when both models were consistent. Implications of these results for the design of methods used to analyze Ames-test data are discussed.

U.S. dietary exposures to heterocyclic amines.

Heterocyclic amines (HAs) formed in fried, broiled or grilled meats are potent mutagens that increase rates of colon, mammary, prostate and other cancers in bioassay rodents. Studies of how human dietary HA exposures may affect cancer risks have so far relied on fairly crudely defined HA-exposure categories. Recently, an integrated, quantitative approach to HA-exposure assessment (HAEA) was developed to estimate compound-specific intakes for particular individuals based on corresponding HA-concentration estimates that reflect their meat-type, intake-rate, cooking-method and meat-doneness preferences. This method was applied in the present study to U.S. national Continuing Survey of Food Intakes by Individuals (CSFII) data on meats consumed and cooking methods used by >25,000 people, after adjusting for underreported energy intake and conditional on meat-doneness preferences estimated from additional survey data. The U.S. population average lifetime time-weighted average of total HAs consumed was estimated to be approximately 9 ng/kg/day, with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) estimated to comprise about two thirds of this intake. Pan-fried meats were the largest source of HA in the diet and chicken the largest source of HAs among different meat types. Estimated total HA intakes by male vs. female children were generally similar, with those by (0- to 15-year-old) children approximately 25% greater than those by (16+-year-old) adults. Race-, age- and sex-specific mean HA intakes were estimated to be greatest for African American males, who were estimated to consume approximately 2- and approximately 3-fold more PhIP than white males at ages <16 and 30+ years, respectively, after considering a relatively greater preference for more well-done items among African Americans based on national survey data. This difference in PhIP intakes may at least partly explain why prostate cancer (PC) kills approximately 2-fold more African American than white men, in view of experimental data indicating that PhIP mutates prostate DNA and causes prostate tumors in rats.

Initial uptake kinetics in human skin exposed to dilute aqueous trichloroethylene in vitro.

In vitro uptake of 14C-labeled trichloroethylene (TCE) from dilute (approximately 5-ppb) aqueous solutions into human surgical skin was measured using accelerator mass spectrometry (AMS). We analyzed 105 breast-tissue samples obtained from three subjects, representing 27 separate exposure experiments conducted at approximately 20 degrees C for 0, 1, 5, 15, 30, or 60 min. The AMS data obtained positively correlate with (p approximately 0) and vary significantly nonlinearly with (p = 0.0094) exposure duration. These data are inconsistent (p approximately 0) with predictions made for TCE by a proposed U.S. Environmental Protection Agency (USEPA) dermal-exposure model, even when uncertainties in its recommended parameter values for TCE are considered, but are consistent (p = 0.17) with a 1-compartment model for exposed skin-surface tissue governed in vitro by a maximum effective permeability of K*p = 0.28 cm h-1 (+/- 7.0%) and a first-order rate constant of k1 = 1.2 h-1 (+/- 16%). The apparent compartment depth is estimated to be approximately 40-100 microns, i.e., to comprise much or all of the epidermis. In contrast, the USEPA model implies only negligible TCE penetration beyond SC during a 1-h exposure. The K*p estimate based on the 1-compartment model fit is consistent with estimates for TCE based on in vivo studies, which supports the hypothesis that the USEPA model underpredicts short-term dermal uptake of TCE from water. It is shown that for humans, this fit also implies that normalized total uptake of TCE from water by short-term dermal contact in vivo is predicted to be fK*p, where f is approximately 80% for longer normothermic exposures and approximately 95% during a brief hot shower or bath. This study illustrates the power of AMS to facilitate analyses of contaminant biodistribution and uptake kinetics at very low environmental concentrations.

Cancer potencies of heterocyclic amines found in cooked foods.

Quantitative estimates of potential cancer risk associated with eating heterocyclic amines (HAs) in cooked foods and food products, known to be highly mutagenic in the Ames/Salmonella assay and to cause cancer in laboratory animals, rely on estimates of carcinogenic potency from animal bioassay data. New estimates of potential human cancer potency are presented for 10 HAs associated with potential human dietary exposure from cooked-food sources. These estimates differ from previous similar estimates in that they properly reflect the fact that most of these HAs exhibit a pronounced ability to induce tumours at multiple histologically distinct sites within each sex/species tested, and so might be expected to be multipotent carcinogens in humans as well. Thus, in addition to 82 tumour-type-specific potencies estimated for these compounds, 24 additional estimates of aggregate potency (to induce one or more tumour types) were made, using different methods to scale estimated bioassay cancer potency to humans. The currently unknown potency of an additional cooked-food HA was estimated using linear regressions of log-carcinogenic on log-mutagenic potency for the other 10 HAs, some of which were highly significant (e.g. r = 0.85, P < 0.004). The potency estimates obtained are consistent with an upper-bound cancer risk between 10(-3) and 10(-4) for an average lifetime cooked-beef intake of 3.3 g/kg/day (or approx. 0.5 lb/day). Use of these potency estimates to obtain more realistic upper-bound estimates of dietary-HA risk will require detailed HA-exposure assessments.

Methods for estimating heterocyclic amine concentrations in cooked meats in the US diet.

Heterocyclic amines (HAs) are formed in numerous cooked foods commonly consumed in the diet. A method was developed to estimate dietary HA levels using HA concentrations in experimentally cooked meats reported in the literature and meat consumption data obtained from a national dietary survey. Cooking variables (meat internal temperature and weight loss, surface temperature and time) were used to develop relationships for estimating total HA concentrations in six meat types. Concentrations of five individual HAs were estimated for specific meat type/cooking method combinations based on linear regression of total and individual HA values obtained from the literature. Using these relationships, total and individual HA concentrations were estimated for 21 meat type/cooking method combinations at four meat doneness levels. Reported consumption of the 21 meat type/cooking method combinations was obtained from a national dietary survey and the age-specific daily HA intake calculated using the estimated HA concentrations (ng/g) and reported meat intakes. Estimated mean daily total HA intakes for children (to age 15 years) and adults (30+ years) were 11 and 7.0 ng/kg/day, respectively, with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) estimated to comprise approximately 65% of each intake. Pan-fried meats were the largest source of HA in the diet and chicken the largest source of HAs among the different meat types.

Mechanistic model predicts a U-shaped relation of radon exposure to lung cancer risk reflected in combined occupational and US residential data.

A mechanistically based cytodynamic two-stage (CD2) cancer model was shown recently to predict both ecologic US county data and underground-miner data on lung-cancer mortality (LCM) vs radon concentration, indicating biological plausibility of the apparent negative dose-response relation exhibited by the ecologic data. To further investigate this hypothesis, the CD2 model was fitted to combine age-specific LCM data vs estimated radon-exposure in white females of age 40+ years in 2821 US counties during 1950-1954 using new estimates of county-specific mean residential radon exposure, and in five cohorts of underground nonsmoking miners. The negative association of radon levels and corresponding county-level LCM rates apparent in women dying in 1950-1954 (11% of whom never smoked) was also apparent in women of age 60+ years (5% of whom never smoked). The CD2 fit obtained to the combined residential and occupational data was found to predict the combined data using biologically plausible parameter values, and also to predict inverse dose-rate effects exhibited in nonsmoking miner data to which the CD2 model was not fit. These results are consistent with the hypothesis that residential radon exposure has a nonlinear U-shaped relation to LCM risk, and that current linear extrapolation models substantially overestimate such risk.

Risk management for plausibly hormetic environmental carcinogens: the case of radon.

Risk management typically involves efforts to reduce human exposures by establishing regulations that limit the concentration of the substance in environmental media. In cases where a substance is widely used in commerce or is naturally occurring in the environment, compliance costs can be substantial because of nationwide requirements to add expensive control technologies. Uncertainties in a dose-response function further impact risk management decisions because they may correspond to large differences in health benefit per unit exposure reduction. These problems are highlighted in the case of plausibly hormetic environmental carcinogens, for which a linear-no-threshold (LNT) dose-response model has been the traditional regulatory default assumption. In this case, model uncertainty is pivotal, and risk management is consequently inherently controversial. However, marginal cost functions that arise for plausibly hormetic carcinogens are expected to possess a common analytic feature that may be particularly useful for this type of risk management problem. Specifically, marginal cost functions in this context are expected to have roots reflecting contaminant concentration values above which regulatory goals may be optimally placed subject to cost constraints. Here we illustrate this heuristic feature in the case of residential radon, using both a LNT model and a biologically plausible hormetic model to predict associated risks of lung cancer mortality.

An updated dose assessment for resettlement options at Bikini Atoll--a U.S. nuclear test site.

On 1 March 1954, a nuclear weapon test, code-named BRAVO, conducted at Bikini Atoll in the northern Marshall Islands contaminated the major residence island. There has been a continuing effort since 1977 to refine dose assessments for resettlement options at Bikini Atoll. Here we provide a radiological dose assessment for the main residence island, Bikini, using extensive radionuclide concentration data derived from analysis of food crops, ground water, cistern water, fish and other marine species, animals, air, and soil collected at Bikini Island as part of our continuing research and monitoring program that began in 1978. The unique composition of coral soil greatly alters the relative contribution of 137Cs and 90Sr to the total estimated dose relative to expectations based on North American and European soils. Without counter measures, 137Cs produces 96% of the estimated dose for returning residents, mostly through uptake from the soil to terrestrial food crops but also from external gamma exposure. The doses are calculated assuming a resettlement date of 1999. The estimated maximum annual effective dose for current island conditions is 4.0 mSv when imported foods, which are now an established part of the diet, are available. The 30-, 50-, and 70-y integral effective doses are 91 mSv, 130 mSv, and 150 mSv, respectively. A detailed uncertainty analysis for these dose estimates is presented in a companion paper in this issue. We have evaluated various countermeasures to reduce 137Cs in food crops. Treatment with potassium reduces the uptake of 137Cs into food crops, and therefore the ingestion dose, to about 5% of pretreatment levels and has essentially no negative environmental consequences. We have calculated the dose for the rehabilitation scenario where the top 40 cm of soil is removed in the housing and village area, and the rest of the island is treated with potassium fertilizer; the maximum annual effective dose is 0.41 mSv and the 30-, 50-, and 70-y integral effective doses are 9.8 mSv, 14 mSv, and 16 mSv, respectively.

Uncertainty and variability in updated estimates of potential dose and risk at a U.S. nuclear test site--Bikini Atoll.

Uncertainty and interindividual variability were assessed in estimated doses for a rehabilitation scenario for Bikini Island at Bikini Atoll, in which the top 40 cm of soil would be removed in the housing and village area, and the rest of the island would be treated with potassium fertilizer, prior to an assumed resettlement date of 1999. Doses were estimated for ingested 137Cs and 90Sr, external gamma-exposure, and inhalation+ingestion of 241Am + 239+240Pu. Two dietary scenarios were considered: imported foods are available (IA); imported foods are unavailable with only local foods consumed (IUA). After approximately 5 y of Bikini residence under either IA or IUA assumptions, upper and lower 95% confidence limits on interindividual variability in calculated dose were estimated to lie within a approximately threefold factor of its in population-average value; upper and lower 95% confidence limits on uncertainty in calculated dose were estimated to lie within a approximately twofold factor of its expected value. For reference, the expected values of population-average dose at age 70 y were estimated to be 16 and 52 mSv under IA and IUA dietary assumptions, respectively. Assuming that 200 Bikini resettlers would be exposed to local foods (under both IA and IUA assumptions), the maximum 1-y dose received by any Bikini resident is most likely to be approximately 2 and 8 mSv under the IA and IUA assumptions, respectively. Under the most likely dietary scenario, involving access to imported foods, this analysis indicates that it is most likely that no additional cancer fatalities (above those normally expected) would arise from the increased radiation exposures considered.

Pharmacokinetics for regulatory risk analysis: the case of trichloroethylene.

Physiologically based pharmacokinetic (PBPK) models describing the uptake, metabolism, and excretion of volatile organic compounds (VOCs) are now proposed for use in regulatory health-risk assessment. A steady-state analysis of one such model is shown to provide simple, convenient predicted relationships between an applied dose and the corresponding toxicologically effective, metabolized dose for certain VOCs like trichloroethylene (TCE). A version of this PBPK model was fit to data on human metabolism of TCE to urinary metabolites in chronically exposed workers, yielding a direct estimate of PBPK parameters governing human capacity to metabolize TCE. It is shown that this estimate is consistent with others based on experimental studies of TCE metabolism in humans exposed to TCE by inhalation for short periods. These results are applied to human cancer-risk assessment using rodent bioassay data on TCE-induced tumorigenesis.

Risk extrapolation for chlorinated methanes as promoters vs initiators of multistage carcinogenesis.

"Cell-kinetic multistage" (CKM) models account for clonal growth of intermediate, premalignant cell populations and thus distinguish somatic mutations and cell proliferation as separate processes that may influence observed rates of tumor formation. This paper illustrates the application of two versions of a two-stage CKM model (one assuming exponential and the other geometric proliferation of intermediate cells) for extrapolating cancer risk potentially associated with exposure to carbon tetrachloride, chloroform, and dichloromethane, three suspect human carcinogens commonly present in trace amounts in groundwater supplies used for domestic consumption. For each compound, the models were used to calculate a daily oral "virtually safe dose" (VSD) to humans associated with a cancer risk of 10(-6), extrapolated from bioassay data on increased hepatocellular tumor incidence in B6C3F1 mice. Exposure-induced bioassay tumor responses were assumed first to be due solely to "promotion" (enhanced proliferation of premalignant cells, here associated with cytotoxicity), in accordance with the majority of available data on in vivo genotoxicity for these compounds. Available data were used to model dose response for induced hepatocellular proliferation in mice for each compound. Physiologically based pharmacokinetic models were used to predict the hepatotoxic effect (metabolized) dose as a function of parent compound administered dose in mice and in humans. Resulting calculated VSDs are shown to be from three to five orders of magnitude greater than corresponding values obtained assuming each of the compounds is carcinogenic only through induced somatic mutations within the CKM framework. Key issues and uncertainties in applying CKM models to risk assessment for cancer promoters are discussed.