Risk assessment for PFOA and kidney cancer based on a pooled analysis of two studies.

INTRODUCTION: Perfluorooctanoic acid (PFOA) has been associated with kidney cancer in human studies. METHODS: We conducted a pooled analysis of two large studies of PFOA and renal cell carcinoma (RCC, the most common type of kidney cancer); one from the National Cancer Institute (NCI) (324 cases and controls), and a second from the C8 Science Panel (103 cases and 511 controls). Serum PFOA levels were estimated a median of 8 years before diagnosis. Analyses were conducted via conditional logistic regression. Lifetime risk of kidney cancer per unit serum PFOA concentration and per unit dose were calculated. RESULTS: The 25th, 50th and 75th percentiles of serum PFOA levels were 4.8, 7.3, and 23.9 ng/ml for the pooled analysis. The preferred model for the pooled datawas a two-piece linear spline model (knot at 12.5 ng/ml serum PFOA); the log odds of RCC increased 0.1349 per 1 ng/ml increase in serum PFOA up to the knot (eg, an OR of 2.02 (1.45-2.80) from the median to the knot), and was flat thereafter. The estimated lifetime excess risk (cancer slope factor) with an exposure of 1 ng/ml was 0.0018, similar to the excess risk of 0.0026 recently reported by CalEPA based on different methods. Assuming a serum half-life of 2.3 years and a distribution volume of 170 ml/kg for PFOA, our results are equivalent to 0.0128 per ng/kg/d of PFOA intake. To limit excess lifetime kidney cancer risk to 1/1,000,000, our data suggest a limit of 0.0015 ng/L (0.0015 ppt) for PFOA in drinking water, similar to CalEPA's proposed Public Health Goal and the new US EPA Drinking Water Health Advisory. CONCLUSIONS: Our results correspond reasonably well with cancer slope factors developed by other investigators using published summary data, and suggest drinking water limits similar to new recommendations by the US EPA.

Do environmental factors affect male fathead minnow (Pimephales promelas) response to estrone? Part 2. Temperature and food availability.

Fish are subject to constantly changing environmental conditions and food availability, factors that may impact their response to endocrine disruptors (EDs). This may, in part, explain outcome discrepancies between field studies and laboratory exposures to EDs. This study assessed whether standard laboratory conditions for fish exposures adequately represent effects of ED exposure at two environmentally realistic temperatures. The impact of temperature and food availability on male fathead minnow response to estrone (E1) exposure was studied in two experiments (3×2×2 factorial design) with three E1 concentrations (range 0-135ng/L); two temperatures (18°C and 26°C, the latter the prescribed laboratory temperature), and two feeding treatments (full fed vs. 25% of full fed) in a 21-day flow-through system. Morphometric endpoints [including body condition factor, somatic index of gonad (GSI) and liver (HSI), and secondary sex characteristics (SSC)], blood parameters [hematocrit (HCT), blood glucose, cortisol, and vitellogenin (VTG) concentrations], and histology of liver and testis were determined on day 22. High E1 consistently increased VTG, though interactions among E1, temperature and/or food on liver weight, HSI, and HCT were inconsistent between experiments. High temperature impacted the greatest number of parameters, independent of E1 treatment. Three sex-linked parameters were lower at high temperature (testis weight, GSI and VTG), and in Exp. 2SSC and gonad maturity rating were lower. At 26°C, in Exp. 1 HSI and HCT decreased, and in Exp. 2 length, body and liver weight, and body condition factor were lower. Food restriction decreased GSI in Exp. 1, and blood glucose and liver weight in Exp. 2. At 26°C several parameters were altered independent of E1 exposure, including three out of four measurements of sperm differentiation. Concordance between laboratory and field investigations of the biological effects of EDs may improve if environmentally-relevant exposure conditions, especially temperature, are employed.

Do laboratory species protect endangered species? Interspecies variation in responses to 17ß-estradiol, a model endocrine active compound.

Although the effects of estrogens on model laboratory species are well documented, their utility as surrogates for other species, including those listed as endangered, are less clear. Traditionally, conservation policies are evaluated based on model organism responses but are intended to protect all species in an environment. We tested the hypothesis that the endangered Rio Grande silvery minnow (Hybognathus amarus) is more vulnerable to endocrine disruption-as assessed through its larval predator-escape performance, survival, juvenile sex ratios, and whole-body vitellogenin concentration-than the commonly used toxicological model species fathead minnow (Pimephales promelas) and the bluegill sunfish (Lepomis macrochirus). Fish were exposed concurrently for 21 days to the model endocrine active compound (EAC) 17ß-estradiol (E2) at 10 ng E2/L and 30 ng E2/L in a flow-through system using reconstituted water that simulated the physicochemical conditions of the Middle Rio Grande in New Mexico, USA. No significant differences were observed between the fathead and silvery minnow in larval predator-escape response or juvenile sex ratio. Rio Grande silvery minnow survival decreased significantly at day 14 compared with the other two species; by day 21, both cyprinid species (silvery minnow and fathead minnow) exhibited a significant decrease in survival compared with bluegill sunfish, a member of the family Centrarchidae. Male Rio Grande silvery minnow showed a significant increase in whole-body vitellogenin concentration in the 10 ng/L treatment, whereas fathead minnow and bluegill sunfish showed no significant increases in vitellogenin concentrations across treatments. Our study showed response differences to estrogen exposures between the two cyprinid species and further divergence in responses between the families Cyprinidae and Centrarchidae. These results suggest that commonly used laboratory model organisms may be less sensitive to EACs than the endangered Rio Grande silvery minnow. However, this study supports the continued use of surrogate species for the beneficial implementation of water-quality regulations for the protection of threatened and endangered species if phylogenetic relationships are taken into consideration.

Predictors of serum polychlorinated biphenyl concentrations in Anniston residents.

The Anniston Community Health Survey was a community-based cross-sectional study of Anniston, Alabama, residents who live in close proximity to a former PCB production facility to identify factors associated with serum PCB levels. The survey comprises 765 Anniston residents who completed a questionnaire interview and provided a blood sample for analysis in 2005-2007. Several reports based on data from the Anniston survey have been previously published, including associations between PCB exposure and diabetes and blood pressure. In this study we examine demographic, behavioral, dietary, and occupational characteristics of Anniston survey participants as predictors of serum PCB concentrations. Of the 765 participants, 54% were White and 45% were African-American; the sample was predominantly female (70%), with a mean age of 55 years. Serum PCB concentrations varied widely between participants (range for sum of 35 PCBs: 0.11-170.4 ng/g wet weight). Linear regression models with stepwise selection were employed to examine factors associated with serum PCBs. Statistically significant positive associations were observed between serum PCB concentrations and age, race, residential variables, current smoking, and local fish consumption, as was a negative association with education level. Age and race were the most influential predictors of serum PCB levels. A small age by sex interaction was noted, indicating that the increase in PCB levels with age was steeper for women than for men. Significant interaction terms indicated that the associations between PCB levels and having ever eaten locally raised livestock and local clay were much stronger among African-Americans than among White participants. In summary, demographic variables and past consumption of locally produced foods were found to be the most important predictors of PCB concentrations in residents living in the vicinity of a former PCB manufacturing facility.

Serum concentrations of polychlorinated biphenyls (PCBs) in participants of the Anniston Community Health Survey.

Serum concentrations of 35 ortho-substituted polychlorinated biphenyl congeners (PCBs) were measured in 765 adults from Anniston, Alabama, where PCBs were manufactured between 1929 and 1971. As part of the Anniston Community Health Survey (ACHS), demographic data, questionnaire information, and blood samples were collected from participants in 2005-2007. Forty-six percent of study participants were African-American, 70% were female, and the median age was 56 years. The median concentration of the sum of 35 PCB congeners (ΣPCBs) was 528 ng/g lipid, with a 90th percentile of 2,600 ng/g lipid, minimum of 17.0 ng/g lipid, and maximum of 27,337 ng/g lipid. The least square geometric mean ΣPCBs was more than 2.5 times higher for African-American participants than for White participants (866 ng/g lipid vs. 331 ng/g lipid); this difference did not change materially after adjustment for age, sex, body mass index (BMI) and current smoking. In spite of large differences in absolute PCB levels, relative contributions of individual congeners to ΣPCBs were quite similar between race groups. Nevertheless, while percent contributions to ΣPCBs for most of the most abundant penta- to heptachlorobiphenyls were higher among African-Americans, the percentages were higher in Whites for the lower-chlorinated PCBs 28 and 74 and for octa- to decachlorinated PCBs. No major differences were observed in geometric mean ΣPCBs between women and men when adjusted for age, race, BMI and current smoking (516 ng/g lipid vs. 526 ng/g lipid). Principal component analysis revealed groups of co-varying congeners that appear to be determined by chlorine substitution patterns. These congener groupings were similar between ACHS participants and the National Health and Nutrition Examination Survey (NHANES) 2003-04 sample of the general United States population, despite ACHS participants having serum concentrations of ΣPCBs two to three times higher than those in comparable age and race groups from NHANES.

Comparing biological effects and potencies of estrone and 17ß-estradiol in mature fathead minnows, Pimephales promelas.

The presence of endocrine active compounds such as estrogens in treated wastewater effluent and their effects on aquatic life are causing concern among aquatic resource managers. In contrast to 17ß-estradiol (E2), the steroid hormone produced by all vertebrates, the biological effects of estrone (E1), one of its breakdown products are less understood, even though the aquatic concentrations of E1 are often higher than those of E2. The central hypothesis of this study was that at environmental concentrations, E1 has estrogenic effects in fish, with increased vitellogenin concentrations and decreased reproductive success in both male and female fathead minnows, as found with E2. In two replicate experiments, we exposed mature fathead minnows to three concentrations of each estrogen for 21 days in a flow-through exposure system and measured a broad suite of anatomical (body indices, histopathology), physiological (plasma vitellogenin), behavioral (nest defense), and reproductive (fecundity, fertility, hatching) endpoints. These endpoints have previously been associated with adverse effects of estrogenic exposures. While body length and weight parameters were unaltered by exposure, secondary sex characteristics exhibited an exposure concentrated-related decline in male fathead minnows. Interestingly, low concentrations of estrone (≈ 15 ng/L) enhanced the aggressiveness of male fathead minnows in a behavioral assay. Vitellogenin concentrations in male fish increased with higher concentrations of both estrogens, but remained unchanged in all female treatments. A decrease in fecundity was observed at high concentrations of E2 as compared with control minnows. These results suggest that E1, at concentrations previously found in waters receiving wastewater effluent, can have reproductive effects on fish.

Comparative biological effects and potency of 17α- and 17ß-estradiol in fathead minnows.

17ß-Estradiol is the most potent natural estrogen commonly found in anthropogenically altered environments and has been the focus of many toxicological laboratory studies. However, fewer aquatic toxicological data on the effects of 17α-estradiol, a diastereoisomer of 17ß-estradiol, exists in the literature even though it has been found in the aquatic environment, sometimes at higher concentrations than 17ß-estradiol. The central objective of this study was to determine how the anatomical, physiological, and behavioral effects of exposure to 17α-estradiol compare to the well-documented effects of 17ß-estradiol exposures in aquatic vertebrates. A 21-day flow-through exposure of mature male and female fathead minnows to three concentrations each of 17α- and 17ß-estradiol (averaged measured concentrations 27, 72, and 150 ng/L for 17α-estradiol, and 9, 20, and 44 ng/L for ß-estradiol, respectively) yielded significant, concentration-dependent differences in plasma vitellogenin concentrations among estradiol-exposed males when compared to fish from an ethanol carrier control. Interstitial cell prominence in the testis of fish was elevated in all estradiol treatments. Aggressiveness of male fish to defend nest sites appeared depressed in many of the higher concentration estradiol treatments (albeit not significantly). No clear effects were observed in female fish. Based on plasma vitellogenin data, it appears that 17ß-estradiol is 8-9 times more potent than 17α-estradiol and that the lowest observable effect concentration (LOEC) for 17α-estradiol in fathead minnows is greater than 25 ng/L and may be less than 75 ng/L.

Assessing the effects of exposure timing on biomarker expression using 17beta-estradiol.

Temporal and spatial variability in estrogenicity has been documented for many treated wastewater effluents with the consequences of this variability on the expression of biomarkers of endocrine disruption being largely unknown. Laboratory exposure studies usually utilize constant exposure concentrations which may produce biological effects that differ from those observed in organisms exposed in natural environments. In this study, we investigated the effects of differential timing of exposures with 17beta-estradiol (E2) on a range of fathead minnow biomarkers to simulate diverse environmentally relevant exposure profiles. Two 21-day, replicate experiments were performed exposing mature male fathead minnows to E2 at time-weighted mean concentrations (similar average exposure to the contaminant during the 21-day exposure period; 17ng E2/L experiment 1; 12ng E2/L experiment 2) comparable to E2 equivalency values (EEQ) reported for several anthropogenically altered environments. A comparable time-weighted mean concentration of E2 was applied to five treatments which varied in the daily application schema: E2 was either applied at a steady rate (ST), in a gradual decreasing concentration (HI), a gradual increasing concentration (LO), applied intermittently (IN), or at a randomly varying concentration (VA). We assessed a range of widely used physiological (vitellogenin mRNA induction and plasma concentrations), anatomical (body and organ indices, secondary sex characteristics, and histopathology), and behavioral (nest holding) biomarkers reported to change following exposure to endocrine active compounds (EACs). All treatments responded with a rise in plasma vitellogenin concentration when compared with the ethanol carrier control. Predicatively, vitellogenin mRNA induction, which tracked closely with plasma vitellogenin concentrations in most treatments was not elevated in the HI treatment, presumably due to the lack of E2 exposure immediately prior to analysis. The ability of treatment male fish to hold nest sites in direct competition with control males was sensitive to E2 exposure and did yield statistically significant differences between treatments and carrier control. Other biological endpoints assessed in this study (organosomatic indices, secondary sex characteristics) varied little between treatments and controls. This study indicates that a broad suite of endpoints is necessary to fully assess the biological consequences of fish exposure to estrogens and that for at least field studies, a combination of vitellogenin mRNA and plasma vitellogenin analysis are most promising in deciphering exposure histories of wild-caught and caged fishes.

An evaluation of surrogate chemical exposure measures and autism prevalence in Texas.

There is currently considerable discussion in the scientific community as well as within the general public concerning the role mercury (Hg) exposures may play in the apparent increased incidence of neurodevelopmental disorders (particularly autism) in children. Although the primary focus of this debate has focused on ethylmercury from vaccinations, linkage to other sources of Hg has been proposed. An ecologic association between 2001 Toxic Release Inventory (TRI; www.epa.gov/tri) data for Hg and 2000-2001 school district autism prevalence was previously reported in Texas. Evaluations using industrial release data as surrogate exposure measures may be problematic, particularly for chemicals like Hg that have complex environmental fates. To explore the robustness of TRI-based analyses of the Hg-autism hypothesis in Texas, a detailed analysis was undertaken examining the extent of the ecological relationship during multiple years and examining whether surrogate exposure measures would yield similar conclusions. Using multilevel Poisson regression analysis and data obtained from a number of publicly available databases, it was found that air Hg release data were significantly associated with autism prevalence in Texas school districts when considering data for 2001 and 2002 (2001: RR = 4.45, 95% CI = 1.60-12.36, 2002: RR = 2.70, 95% CI = 1.17-6.15). Significant associations were not found using data from 2003 to 2005. A significant association was not observed when considering air Hg data for 2000 or 2001 and school district autism prevalence data for 2005-2006 or 2006-2007, an analysis allowing for a 5-yr time period between presumed exposure and entry into the public school system (2000: RR = 1.03, 95% CI = 0.59-1.83, 2001: RR = 0.94, 95% CI = 0.59-1.47). Significant associations were not observed for any year nor for the time lagged analyses when censored autism counts were replaced by threes instead of zeros. An evaluation of TRI air emissions data for several other pollutants did not find significant associations except for nickel (RR = 1.71, 1.12-2.60), which has no history of being associated with neurodevelopmental disorders. An evaluation using downwind location from coal-fired power plants as the exposure surrogate variable also did not yield statistically significant results. The analysis suggests Hg emissions are not consistently associated with autism prevalence in Texas school districts. The lack of consistency across time may be the result of the influence of a more significant factor which remains unidentified. Alternatively, it may be that the significant association observed in 2001 and 2002 does not represent a true causal association.

CART deficiency increases body weight but does not alter bone strength.

The regulation of bone metabolism mediated by leptin is a complex process that is not clearly understood. Recent studies suggest that CART (cocaine-amphetamine related transcript) is a significant neuronal co-factor when combined with leptin. CART deficiency is thought to result in low trabecular bone mass, but since leptin exerts contrasting effects on trabecular and cortical bone it is possible that cortical bone may not respond to the absence of CART signaling in the same manner as trabecular bone. We tested the hypothesis that CART deficiency decreases cortical bone mass, density, and strength by examining femora of adult wild-type mice (CART(+/+)) and CART-deficient mice (CART(-/-)). DEXA densitometry (PIXImus system) was used to measure whole-bone mineral content (BMC) and mineral density (BMD) from right femora, and pQCT used to calculate densitometric and geometric parameters from the femur midshaft. Femora were also tested in three-point bending, and sections of the tibia analyzed histologically to determine bone marrow adipocyte density (N.At./M.Ar) and endocortical osteoclast number (N.Oc/B.Pm). The control mice weighed less than the mice lacking CART (P<0.001), but mechanical testing data showed no differences (p>0.05) in ultimate force, energy to fracture, stiffness, or intrinsic properties such as ultimate stress, ultimate strain, or modulus. CART-deficient mice did not differ from normal controls in whole-femur BMC (p=0.09), BMD (p=0.19), midshaft cortical bone thickness (p=0.67), midshaft cortical bone area (p=0.59) or N.Oc/B.Pm (p=0.94), although CART deficiency was associated with a three-fold increase in bone marrow adipocyte density (p<0.001). Our data suggest that while the central, neuroendocrine regulation of bone mass via CART signaling may have effects on trabecular mass, absence of CART expression does not significantly alter cortical bone geometry, density, or strength.

Impairment of the reproductive potential of male fathead minnows by environmentally relevant exposures to 4-nonylphenolf.

The synthetic organic compound 4-nonylphenol (NP) has been detected in many human-impacted surface waters in North America. In this study, we examined the ability of NP to alter reproductive competence in male fathead minnows after a 28 day flow-through exposure in a range of environmentally relevant concentrations bracketing the U.S. Environmental Protection Agency toxicity-based NP chronic exposure criterion of 6.1 microg NP/L. Exposure to NP at and above the EPA chronic exposure criterion resulted in an induction of plasma vitellogenin (VTG) within 14 days. However, 7 days after the cessation of exposure, VTG concentrations had dropped more than 50% and few males expressed VTG above the detection threshold. All of the morphological endpoints, including gonadosomatic index, hepatosomatic index, secondary sexual characters, and histopathology, were unaltered by all NP treatments. However, when NP-exposed male fish were allowed to compete with control males for access to nest sites and females, most treatments altered the reproductive competence of exposed males. At lower NP concentrations, exposed males out-competed control males, possibly by being primed through the estrogenic NP exposure in a fashion similar to priming by pheromones released from female fathead minnows. At higher NP exposure concentrations, this priming effect was negated by the adverse effects of the exposure and control males out-competed treated males. Results of this study indicate the complexity of endocrine disrupting effects and the need for multiple analysis levels to assess the effects of these compounds on aquatic organisms.

The effect of supplemental glutamine on growth performance, development of the gastrointestinal tract, and humoral immune response of broilers.

Two experiments were conducted to evaluate the effect of supplemental Gln on growth performance, development of the gastrointestinal tract, and humoral immune response of broilers. Immediately after hatch 6 replicate pens of 6 chicks were randomly assigned to 1 of 7 (experiment 1) or 5 (experiment 2) dietary treatments for 21 d. On d 4, 7, 14, and 21, twelve chicks per treatment (2 chicks/pen) were killed for thymus, spleen, bursa, duodenum, jejunum, ileum, bile, and blood sample collections and weights. In experiment 1, the effect of 1 or 4% Gln addition to the feed, water, or both was compared with a corn-soybean meal (SBM) control diet. All diets were formulated to be isocaloric and isonitrogenous. Weight gain improved significantly (P < 0.05) when chicks were fed diets with 1% Gln as compared with chicks fed the control diet (11% average improvement). The addition of 4% Gln to the diet or water depressed (P < 0.05) growth performance. Based on the results from experiment 1, 1% Gln supplementation to the diet was determined to be ample and most practical. Thus in experiment 2, diets supplemented with 1% Gln were fed for 4, 7, 14, or 21 d after which time chicks were fed the corn-SBM control diet until the experiment was terminated at 21 d. Weight gain improved significantly (P < 0.05) when chicks were fed diets supplemented with 1% Gln throughout the 21-d study. In both experiments, chicks fed diets supplemented with 1% Gln for 21 d had higher concentrations of bile, intestinal, and sera IgA and sera IgG (P < 0.05). Chicks fed diets with 1% Gln had heavier intestinal relative weights and longer intestinal villi (P < 0.05) as compared with the chicks fed the corn-SBM diet. Our results indicate that the addition of 1% Gln to the diet of broiler chicks improves growth performance and may stimulate development of the gastrointestinal tract and humoral immune response.

Comparative risk and policy analysis in environmental health.

There is increasing interest in the integration of quantitative risk analysis with benefit-cost and cost-effectiveness methods to evaluate environmental health policy making and perform comparative analyses. However, the combined use of these methods has revealed deficiencies in the available methods, and the lack of useful analytical frameworks currently constrains the utility of comparative risk and policy analyses. A principal issue in integrating risk and economic analysis is the lack of common performance metrics, particularly when conducting comparative analyses of regulations with disparate health endpoints (e.g., cancer and noncancer effects or risk-benefit analysis) and quantitative estimation of cumulative risk, whether from exposure to single agents with multiple health impacts or from exposure to mixtures. We propose a general quantitative framework and examine assumptions required for performing analyses of health risks and policies. We review existing and proposed risk and health-impact metrics for evaluating policies designed to protect public health from environmental exposures, and identify their strengths and weaknesses with respect to their use in a general comparative risk and policy analysis framework. Case studies are presented to demonstrate applications of this framework with risk-benefit and air pollution risk analyses. Through this analysis, we hope to generate discussions regarding the data requirements, analytical approaches, and assumptions required for general models to be used in comparative risk and policy analysis.

A computational model for neocortical neuronogenesis predicts ethanol-induced neocortical neuron number deficits.

We have developed a computational model that allows for the evaluation of normal and perturbed neurodevelopmental processes. This mathematical construct is used to test the hypothesis that reduced neuronal production is the critical mechanism behind fetal alcohol syndrome. Model predictions of normal neurodevelopment match independent stereological measures but challenge estimates generated using a previously published model of normal neocortical neuronogenesis. Evaluation of data showing an increased cell cycle length after prenatal exposure to ethanol during neocortical neuronogenesis yields predictions of cellular deficits that can account for the permanent neocortical neuronal loss seen in rodents exposed to ethanol concentrations of public health relevance.

Effects of uncertainties on exposure estimates to methylmercury: a Monte Carlo analysis of exposure biomarkers versus dietary recall estimation.

This article presents a general model for estimating population heterogeneity and "lack of knowledge" uncertainty in methylmercury (MeHg) exposure assessments using two-dimensional Monte Carlo analysis. Using data from fish-consuming populations in Bangladesh, Brazil, Sweden, and the United Kingdom, predictive model estimates of dietary MeHg exposures were compared against those derived from biomarkers (i.e., [Hg]hair and [Hg]blood). By disaggregating parameter uncertainty into components (i.e., population heterogeneity, measurement error, recall error, and sampling error) estimates were obtained of the contribution of each component to the overall uncertainty. Steady-state diet:hair and diet:blood MeHg exposure ratios were estimated for each population and were used to develop distributions useful for conducting biomarker-based probabilistic assessments of MeHg exposure. The 5th and 95th percentile modeled MeHg exposure estimates around mean population exposure from each of the four study populations are presented to demonstrate lack of knowledge uncertainty about a best estimate for a true mean. Results from a U.K. study population showed that a predictive dietary model resulted in a 74% lower lack of knowledge uncertainty around a central mean estimate relative to a hair biomarker model, and also in a 31% lower lack of knowledge uncertainty around central mean estimate relative to a blood biomarker model. Similar results were obtained for the Brazil and Bangladesh populations. Such analyses, used here to evaluate alternative models of dietary MeHg exposure, can be used to refine exposure instruments, improve information used in site management and remediation decision making, and identify sources of uncertainty in risk estimates.

Human variability in mercury toxicokinetics and steady state biomarker ratios.

Regulatory guidelines regarding methylmercury exposure depend on dose-response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose-response models. Most assessments have used point estimates for these ratios; however, significant interindividual and interstudy variability has been reported. For example, a maternal ratio of 250 ppm in hair per mg/L in blood is commonly used in models, but a 1990 WHO review reports mean ratios ranging from 140 to 370 ppm per mg/L. To account for interindividual and interstudy variation in applying these ratios to risk and safety assessment, some researchers have proposed representing the ratios with probability distributions and conducting probabilistic assessments. Such assessments would allow regulators to consider the range and like-lihood of mercury exposures in a population, rather than limiting the evaluation to an estimate of the average exposure or a single conservative exposure estimate. However, no consensus exists on the most appropriate distributions for representing these parameters. We discuss published reviews of blood-to-hair and blood-to-intake steady state ratios for mercury and suggest statistical approaches for combining existing datasets to form generalized probability distributions for mercury distribution ratios. Although generalized distributions may not be applicable to all populations, they allow a more informative assessment than point estimates where individual biokinetic information is unavailable. Whereas development and use of these distributions will improve existing exposure and risk models, additional efforts in data generation and model development are required.

Use of quality-adjusted life year weights with dose-response models for public health decisions: a case study of the risks and benefits of fish consumption.

Risks associated with toxicants in food are often controlled by exposure reduction. When exposure recommendations are developed for foods with both harmful and beneficial qualities, however, they must balance the associated risks and benefits to maximize public health. Although quantitative methods are commonly used to evaluate health risks, such methods have not been generally applied to evaluating the health benefits associated with environmental exposures. A quantitative method for risk-benefit analysis is presented that allows for consideration of diverse health endpoints that differ in their impact (i.e., duration and severity) using dose-response modeling weighted by quality-adjusted life years saved. To demonstrate the usefulness of this method, the risks and benefits of fish consumption are evaluated using a single health risk and health benefit endpoint. Benefits are defined as the decrease in myocardial infarction mortality resulting from fish consumption, and risks are defined as the increase in neurodevelopmental delay (i.e., talking) resulting from prenatal methylmercury exposure. Fish consumption rates are based on information from Washington State. Using the proposed framework, the net health impact of eating fish is estimated in either a whole population or a population consisting of women of childbearing age and their children. It is demonstrated that across a range of fish methylmercury concentrations (0-1 ppm) and intake levels (0-25 g/day), individuals would have to weight the neurodevelopmental effects 6 times more (in the whole population) or 250 times less (among women of child-bearing age and their children) than the myocardial infarction benefits in order to be ambivalent about whether or not to consume fish. These methods can be generalized to evaluate the merits of other public health and risk management programs that involve trade-offs between risks and benefits.

Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention.

Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

PARATI--a dynamic model for radiological assessments in urban areas. Part III: Parameter uncertainty analysis.

The uncertainties in the exposure predictions after contamination of an urban area due to the variabilities in environmental transfer parameters and in dose conversion factors have been estimated. This was done using the "Latin Hypercube" sampling scheme and the computer codes PRISM and PARATI. For the scenario 'urban contamination by 137Cs' and the population groups considered, the main sources contributing to the uncertainty in the resulting exposures are the limited knowledge of the initial deposition and retention, the weathering processes, the actual urban environments, and the characteristics and habits of the population. The effect of the parameter uncertainties on the variability of the dose is almost constant over time.