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Problems facing the decision-maker in the risk assessment process.

This paper presents an overview of the U.S. Environmental Protection Agency's risk assessment process, describes problems that the Agency faces in conducting risk assessment, in general, and identifies some specific problems that the Agency confronts when conducting risk assessments on suspected developmental toxicants. As noted by the NAS (National Research Council: "Risk Assessment in the Federal Government: Managing the Process." Washington, DC: National Academy Press, 1983, pp 17-83), improving the quality and comprehensiveness of knowledge is the most effective way to improve risk assessment, but some limitations are inherent and may remain unresolvable. Therefore, inferences will always be required. The Agency's challenge is to ensure that these inferences are as soundly based as possible.

Dose-Response Relationship, Drug↗

Leaching and toxicity behavior of coal-biomass waste cocombustion ashes.

Land disposal of ash residues, obtained from the cocombustion of Greek lignite with biomass wastes, is known to create problems due to the harmful constituents present. In this regard, the leachability of trace elements from lignite, biomass, and blends cocombustion ashes was investigated by using the Toxicity Characteristic Leaching Procedure (TCLP) of the US Environmental Protection Agency (US EPA). In this work, the toxicity of the aqueous leachates and the concentrations of the metals obtained from the leaching procedure were measured using the Microtox test (Vibrio fischeri) and inductive coupled plasma-atomic emission spectrometer (ICP-AES), respectively. The toxic effects of most leachates on Vibrio fischeri were found to be significantly low in both 45% and 82% screening test protocols. However, the liquid sample originating from olive kernels fly ash (FA4) caused the highest toxic effect in both protocols, which can be attributed to its relatively high concentrations of As, Cd, Co, Cu, Mn, Ni, and Zn.

Aliivibrio fischeri↗

Validation of some extrapolation methods with toxicity data derived from multiple species experiments.

For effects assessment several extrapolation methods are used which can be applied to estimate the concentration of toxic chemicals above which ecosystems may be affected. At present, however, it is uncertain whether the values calculated with these methods really represent concentrations harmless to ecosystems. Therefore, a validation is carried out by comparing no-observed-effect concentrations derived from multiple species experiments with extrapolated values. In this study validation was restricted to the methods of Aldenberg and Slob (1993) and Wagner and Løkke (Water Res. 25, 1237-1242, 1991), and a modification of the method of the Environmental Protection Agency (Slooff, 1992). Also, only organic compounds were studied. With restrictions, due to the paucity of data, it is concluded that single species toxicity data are a good starting point for establishing "safe" values for the aquatic ecosystem. Furthermore, extrapolation methods seem to be a good basis for determining these values if sufficient toxicity data are available for sensitive taxonomic groups. From the results of this study it was not possible to give preference to one of the validated extrapolation methods, but on theoretical ground the methods of Aldenberg and Slob and Wagner and Løkke are perferred.

Animals↗

Culturing and bioassay testing of Daphnia magna using Elendt M4, Elendt M7, and COMBO media.

A performance-based, tiered approach was used to evaluate survival, growth, and reproduction of Daphnia magna in three selected synthetic media: Elendt M4, Elendt M7, and COMBO. Both Elendt M4 and Elendt M7 are high-hardness media currently recommended for Organization for Economic Cooperation and Development (OECD) testing. COMBO is a softer medium similar in total hardness to natural water found in the environment. Tier I consistent of an acclimation phase; Tier II involved a 21-day evaluation of survival, growth, and reproduction; and Tier III used each medium in a 21-day chronic study using a reference toxicant, 3,4-dichloroaniline (3,4-DCA). The evaluation of the performance of each medium was based on acceptance criteria similar to those used by the U.S. Environmental Protection Agency and the European Commission. Tests were run concurrently at three laboratories to assess interlaboratory variability. Daphnids were acclimated to the media for less than 1 month. Daphnid performance in all media exceeded the European Economic Community (EEC) validity criteria; however, reproductive performance and growth were significantly greater in the Elendt media than in COMBO. 3,4-DCA exerted more toxicity to daphnids in COMBO medium [no-observed-effect concentration (NOEC), <3.1microg/liter] compared with those in the Elendt media (NOEC, </=8.8 microg/liter). Elendt M7 medium provided the most consistent NOECs between laboratories (3. 1-8.8 microg/liter). However, results from two of three laboratories indicated decreases in fecundity over time in all media. The use of synthetic media for long-term culturing and bioassay testing of D. magna is still in question.

Animals↗

Log-additive versus log-linear analysis of lead-contaminated house dust and children's blood-lead levels. Implications for residential dust-lead standards.

The Environmental Protection Agency has been mandated to develop a health-based standard for lead in residential dwellings in the United States. Prior estimates of the relationship between residential dust-lead levels and children's blood-lead concentrations have usually been obtained by using a log-linear regression of blood-lead concentration on levels of lead-contaminated house dust. It remains unknown, however, whether the log-linear model or a frequently cited alternative, the log-additive model, is the preferable regression method for analyzing these data. Secondary analysis of the Lead-in-Dust Study data was undertaken to compare log-additive with log-linear regression analysis for the purpose of developing a health-based dust lead standard. Specifically, we were interested in comparing the log-additive and log-linear analyses in their ability to characterize adequately the relationship of dust-lead loading on various surfaces with blood-lead concentrations among urban children and to develop a predictive model to estimate the risk that a child will develop an elevated blood-lead level on the basis of a known level of dust lead. We used two dust sampling methods, the Baltimore Repair and Maintenance (BRM) vacuum method and the wipe method, to compare the log-linear and log-additive models. The log-linear model was consistently superior to the log-additive model in its ability to explain the variability in the observed blood-lead concentrations of the studied children, for both the wipe sampler and the BRM sampler. In addition, the log-additive model often predicted only a limited increase in the probability of blood-lead concentrations exceeding 10 micrograms/dl as a result of doubling the dust-lead loading exposure, whereas the log-linear model consistently demonstrated a significant increase in the probability of blood-lead concentrations exceeding 10 micrograms/dl. BRM lead loading explained additional variability in blood lead above and beyond that explained by wipe loading for both carpeted and uncarpeted floors. In contrast, wipe-lead loading explained significant additional variability after adjustment for BRM loading for both uncarpeted floors and interior window sills. Although BRM loading better predicted children's blood-lead concentrations than did wipe loading, these differences were not statistically significant. We conclude that the log-linear model explained a greater percentage of the variability in blood-lead concentrations than did the log-additive model, indicating that the log-linear model should be the default model of choice for developing a dust-lead standard.

Air Pollution, Indoor↗

Influence of bone-lead stores on the observed effectiveness of lead hazard intervention.

Lead hazard interventions have reduced children's blood-lead concentrations, but do not eliminate lead altogether from the bloodstream. Several studies suggest that blood-lead concentrations, measured 6 to 12 months after such interventions, decline by approximately 25%. The Environmental Protection Agency is preparing to promulgate a rule prescribing residential lead levels in paint, dust, and soil that constitute a lead-based paint hazard. Such a rule will prompt interventions of primary prevention character (i.e., precluding exposure before it occurs) rather than the secondary prevention character interventions (i.e., alleviating exposure after it has adversely affected the resident child) documented in the literature. It is important to attempt to estimate the efficacy achieved from the primary prevention interventions prompted by the rule's promulgation. As bone-lead stores represent the principal confounding factor to relating secondary prevention results to primary prevention, this paper addresses the impact of lead stored in bone, which may later be released to the blood and other parts of the child's body. A simple, but thoroughly documented, modeling exercise is presented to estimate the maximum length of time for which bone-lead stores alone could account for continuing elevated blood-lead levels observed in children following an intervention. The approach is based on a two-compartment model for the transfer of lead between blood and bone tissues within the body and the elimination of lead from the body. Modeling results suggest that bone-lead mobilization can impact blood-lead levels of young children for considerably long periods following an intervention. These results may explain the seemingly contradictory fact that low declines in blood-lead concentrations are observed despite the significant reduction in residential dust-, paint-, and soil-lead levels observed following lead hazard interventions. An intervention which reduces a 5-year-old child's total lead exposure by 50% might, due to mobilized bone-lead stores, produce only a 25% decline in the child's blood-lead concentrations measured 12 months following the intervention. The results also suggest, however, that those intervention strategies for which less than 25% declines were observed 12 months following the intervention likely eliminated less than 50% of the children's total lead exposure.

Bone and Bones↗

Estimating cancer risk from outdoor concentrations of hazardous air pollutants in 1990.

A public health concern regarding hazardous air pollutants (HAPs) is their potential to cause cancer. It has been difficult to assess potential cancer risks from HAPs, due primarily to lack of ambient concentration data for the general population. The Environmental Protection Agency's Cumulative Exposure Project modeled 1990 outdoor concentrations of HAPs across the United States, which were combined with inhalation unit risk estimates to estimate the potential increase in excess cancer risk for individual carcinogenic HAPs. These were summed to provide an estimate of cancer risk from multiple HAPs. The analysis estimates a median excess cancer risk of 18 lifetime cancer cases per 100,000 people for all HAP concentrations. About 75% of estimated cancer risk was attributable to exposure to polycyclic organic matter, 1,3-butadiene, formaldehyde, benzene, and chromium. Consideration of some specific uncertainties, including underestimation of ambient concentrations, combining upper 95% confidence bound potency estimates, and changes to potency estimates, found that cancer risk may be underestimated by 15% or overestimated by 40-50%. Other unanalyzed uncertainties could make these under- or overestimates larger. This analysis used 1990 estimates of concentrations and can be used to track progress toward reducing cancer risk to the general population.

Adolescent↗

A 90-day chloroform inhalation study in female and male B6C3F1 mice: implications for cancer risk assessment.

High doses of chloroform induced liver cancer in male and female B6C3F1 mice when administered by gavage, kidney cancer in male Osborne-Mendel rats when given by gavage or in the drinking water, and kidney cancer in male BDF1 mice when administered by inhalation. The weight of evidence indicates that chloroform is acting through a nongenotoxic-cytotoxic mode of action. The present study was designed to investigate the dose-response relationships for chloroform-induced lesions and regenerative cell proliferation in B6C3F1 mice as the basis for formulation of a biologically based risk assessment for inhaled chloroform. Different groups of female and male B6C3F1 mice were exposed to atmospheric concentrations of 0, 0.3, 2, 10, 30, and 90 ppm chloroform 6 hr/day, 7 days/week for exposure periods of 4 days or 3, 6, or 13 consecutive weeks. Some additional exposure groups were exposed for 5 days/week for 13 weeks or were exposed for 6 weeks and then examined at 13 weeks. Bromodeoxyuridine was administered via osmotic pumps implanted 3.5 days prior to necropsy, and the labeling index (LI, percentage of nuclei in S-phase) was evaluated immunohistochemically from histological sections. Complete necropsy and microscopic evaluation revealed treatment-induced dose- and time-dependent lesions only in the livers and nasal passage of the female and male mice and in the kidneys of the male mice. Large, sustained increases in the liver LI were seen in the 90-ppm groups at all time points. The female mice were most sensitive, with a no-observed-adverse-effect level (NOAEL) for induced hepatic cell proliferation of 10 ppm. The hepatic LI in the 5 days/week groups were about half of those seen in the 7 days/week groups and had returned to the normal baseline in the 6-week recovery groups. Induced renal histologic changes and regenerative cell proliferation were seen in the male mice at 30 and 90 ppm with 7 days/week exposures and also at 10 ppm with the 5 days/week regimen. Nasal lesions were transient and confined to mice exposed to 10, 30, or 90 ppm for 4 days. In a previous cancer bioassay, a gavage dose of 477 mg/kg/day produced a 95% liver tumor incidence in female B6C3F1 mice. This gavage dose is equivalent to a daily 6 hr/day inhalation exposure of approximately 80 ppm, based on the observed induced increases in the LI as an internal dosimeter. The United States Environmental Protection Agency currently uses the linearized multistage model applied to the mouse liver tumor data from the chloroform gavage study to estimate a virtually safe dose (VSD) as a one in a million increased lifetime risk of cancer. The resulting value is an airborne exposure concentration of 0.000008 ppm. Assuming that chloroform-induced female mouse liver cancer is secondary to events associated with necrosis and regenerative cell proliferation, then no increases in liver cancer in female mice would be predicted at the NOAEL of 10 ppm or below based on the results reported here. Applying an uncertainty factor of 1000 yields an estimate of a VSD at 0.01 ppm. This estimate relies on inhalation data and is more consistent with the mode of action of chloroform.

Administration, Inhalation↗

Human red blood cell acetylcholinesterase inhibition as the appropriate and conservative surrogate endpoint for establishing chlorpyrifos reference dose.

Chlorpyrifos (O,O-diethyl O-(3,5, 6-trichloro-2-pyridinyl)- phosphorothioate) is an organophosphorus (OP) insecticide used for controlling insect pests. Currently, the reference dose (RfD) used by the Environmental Protection Agency (EPA) to establish acceptable human exposure tolerances for chlorpyrifos is based upon inhibition of blood butyrylcholinesterase (BuChE), which is not the target enzyme of chlorpyrifos, and does not play any role in cholinergic transmission. Data are presented showing that inhibition of acetylcholinesterase (AChE) associated with red blood cells (RBC), an enzyme similar to or identical with that in the nervous system, is a more appropriate endpoint on which to base the RfD. Basing an acceptable level of human exposure (e.g., RfD) on inhibition of RBC AChE provides a significant margin of safety, since it is 12- to 14-fold more sensitive as an indicator of chlorpyrifos exposure than the AChE in the most sensitive relevant neurological tissues (brain or retina). Inhibition of RBC AChE activity is consistently exhibited at lower dosages of chlorpyrifos than those required to result in clinical symptoms of OP toxicity, or alterations in cognitive functional responses. There is no unique sensitivity of the fetus or neonates to chlorpyrifos when administered by an appropriate oral dose. Thus, inhibition of RBC AChE activity is an appropriate surrogate measurement of chlorpyrifos exposure and provides a conservative endpoint for establishing appropriate margins of safety for both adults and infants.

Adult↗

Regulatory cancer risk assessment based on a quick estimate of a benchmark dose derived from the maximum tolerated dose.

The proposed U.S. Environmental Protection Agency carcinogen risk assessment guidelines employ a benchmark dose as a point of departure (POD) for low-dose risk assessment. If information on the carcinogenic mode of action for a chemical supports a nonlinear dose-response curve below the POD, a margin-of-exposure ratio between the POD and anticipated human exposure would be considered. The POD would be divided by uncertainty (safety) factors to arrive at a reference dose that is likely to produce no, or at most negligible, cancer risk for humans. If nonlinearity below the POD is not supported by sufficient evidence, then linear extrapolation from the incidence at the POD to zero would be used for low-dose cancer risk estimation. The carcinogen guidelines suggest that the lower 95% confidence limit on the dose estimated to produce an excess of tumors in 10% of the animals (LTD10) be used for the POD. Due to the relatively narrow range of doses in 2-year rodent bioassays and the limited range of statistically significant tumor incidence rates, the estimate of the LTD10 obtained from 2-year bioassays is constrained to a relatively narrow range of values. Because of this constraint, a simple, quick, and relatively precise determination of the LTD10 can be obtained by the maximum tolerated dose (MTD) divided by 7. All that is needed is a 90-day study to establish the MTD. It is shown that the LTD10 determined by this relatively easy procedure is generally within a factor of 10 of the LTD10 that would be estimated using tumor incidence rates from 2-year bioassays. Estimates of cancer potency from replicated 2-year bioassays, and hence estimates of cancer risk, have been show to vary by a factor of 4 around a median value. Thus, there may be little gain in precision of cancer risk estimates derived from a 2-year bioassay, compared to the estimate based on the MTD from a 90-day study. If the anticipated human exposure were estimated to be small relative to the MTD/7 = LTD10, there may be little value in conducting a chronic 2-year study in rodents because the estimate of cancer risk would be low regardless of the results of a 2-year bioassay. Linear extrapolation to a risk of less than 1 in 100,000 and use of an uncertainty factor, e.g., of 10,000, would give the same regulatory "safe dose." Linear extrapolation to a virtually safe dose associated with a cancer risk estimate of less than one in a million would be 10 times lower than the reference dose based on the LTD10/10,000.

Benchmarking↗

An FDA review of sulfamethazine toxicity.

Recently, changes have been proposed in the criteria historically used in the evaluation of the applicability to humans of some of the results obtained from the rodent carcinogenicity bioassay data. These questions center on the suitability of the rodent model for agents that exert their toxic effects via specific enzyme interactions and endocrine mechanisms which appear to be inoperative within humans. Within the U.S. Food and Drug Administration (FDA), this issue has been brought to the forefront of concern with the recent application for a New Animal Drug Application for sulfamethazine (SMZ). A panel of FDA experts from the National Center for Toxicological Research (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Food Safety and Applied Nutrition has reviewed the sum of the scientific evidence available on the toxicology of SMZ. They noted that, in previous feeding studies at NCTR, high doses of SMZ were associated with significant incidences of thyroid tumors in mice and rats. The panel also notes that the tumorigenic activity of SMZ in rodents was due to its goitrogenic activity, resulting in constant stimulation of the thyroid by TSH. Humans, on the other hand, were found to be insensitive to the SMZ-like inhibition of thyroid function. Further, apart from X-irradiation and radioactive iodine, there are no other physical or chemical agents known to cause thyroid tumors in humans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This conclusion is in agreement with recommendations made by three other panels, viz. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.

Animals↗

Using human data to protect the public's health.

The value of using human data in the assessment and management of risk is evaluated. Although the use of such data has a long and successful history with environmental contaminants and the development of drugs and commercial chemicals, recent deliberations within the Environmental Protection Agency (EPA) have questioned this practice in part. Specifically, we evaluate the degree to which reference doses (RfDs) and reference concentrations (RfCs) derived from human data on EPA's Integrated Risk Information System (IRIS) differ with RfDs and RfCs that we estimate from experimental animal data. We also use several minimal risk levels of the Agency for Toxic Substances and Disease Registry (ATSDR) and tolerable intakes of Health Canada in this comparison. Human-based RfDs are more than threefold lower than the corresponding animal-based RfDs for 23% of the comparisons. Human- based RfDs or RfCs are lower than corresponding animal-based RfDs or RfCs for 36% of the comparisons. Furthermore, for 10 of 43 possible comparisons, insufficient experimental animal data are readily available or data are inappropriate to estimate either RfDs or RfCs. We also discuss human pharmacokinetic data from volunteer studies and mechanistic studies with human tissues in vitro and demonstrate through a series of case discussions that utilization of such data is important when making decisions to protect exposed individuals. Moreover, physiologically based pharmacokinetic (PBPK) modeling evaluates critical information in assessing interindividual variability and identifying at-risk populations. Within the limits of our analysis, we conclude that the direct use and interpretation of human data, in conjunction with data gathered from experimental animals, are public health protective policies that should be encouraged.

Animals↗

Polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans and birth weight and immune and thyroid function in children.

None of the publications reviewed provide clinical evidence that PCBs (polychlorinated biphenyls) and related chemicals adversely affect weight, immune, or thyroid function in infants or children born to healthy mothers. Birth weights of term infants fell within the normal range in all studies. The greatest difference between comparison groups was reported by G. G. Fein et al. (1984a, Intrauterine Exposure of Humans to PCBs: Newborn Effects, EPA-600/3-84-060, Environmental Protection Agency; 1984b, J. Pediatr. 105, 315-320). P. R. Taylor et al. (1989, Am. J. Epidemiol. 129, 395-406) reported smaller differences in occupationally exposed women and E. Dar et al. (1992, Environ. Res. 59, 189-201) found that women with higher PCB serum levels had larger babies. S. Patandin et al. (1998, Pediatr Res. 44, 538-545) found a negative association of PCB concentrations in maternal or cord plasma and birth weight of breast and formula-fed infants combined but not when breast-fed infants were analyzed separately. L. Rylander et al. (1995, Scand. J. Work Environ. Health 21, 368-375) reported decreased birth weights with higher dietary intake of contaminated fish. Thus, correlations between PCB exposure or polluted fish ingestion and birth weight were inconsistent. Thyroid and immune function were also within the normal range. In none of the papers were normal laboratory reference values provided and overall the statistically significant differences accounted for little of the variance.

Benzofurans↗

Dermal absorption in rhesus monkeys of polychlorinated biphenyls from soil contaminated with Aroclor 1260.

Human health risk assessments involving contaminated soil include dermal absorption as a potential pathway contributing to the total exposure burden. For PCB-contaminated soil, the U.S. Environmental Protection Agency uses a dermal absorption factor of 14%, based on a 1993 study of dermal absorption in rhesus monkeys. The current study examined several parameters that can influence the dermal absorption of lipophilic hydrocarbons, including soil organic content, particle size, skin residence time, and contaminant "aging" in the soil. Four groups of four female rhesus monkeys each were exposed to radiolabeled Aroclor 1260 either intravenously (100% absorption) or dermally with PCB-spiked soil. Groups exposed for 12 or 24 h to PCBs aged in soil exhibited percutaneous absorption values of 3.43 +/- 0.35 and 4.26 +/- 0.52%, respectively, while a group exposed for 24 h to soil freshly spiked with PCBs exhibited a dermal absorption value of 4.07 +/- 0.46%. Evidence strongly suggests that the factor most responsible for modulating the percutaneous absorption of highly lipophilic compounds from soil is its organic content. The base soil used in the current study with Aroclor 1260 had an organic content of 5-6% (< or =2 mm particle fraction), a value typical for U.S. soil. The organic content of the soil applied to the skin was 8.7% (<150 microm particle fraction), a value that contrasts sharply with the soil containing 0.9% organics used in the 1993 study with Aroclors 1242 and 1254 that produced a dermal absorption value of 14% for PCBs.

Administration, Cutaneous↗

Acute pesticide morbidity and mortality: California.

The California Pesticide Illness Surveillance Program collects, investigates, abstracts, and records reports received from physicians. A minority of the reports are received through the county health officers who are notified by physicians under a state requirement for reporting pesticide-caused conditions. Most of the cases are identified by review of workers' compensation records. All the cases identified are investigated by the agricultural commissioners of the counties where exposure occurred. The investigation reports are reviewed and abstracted by staff of the Worker Health and Safety Branch of the California Department of Pesticide Regulation, California Environmental Protection Agency (Cal/EPA). The crucial determination is assessment of the degree of relationship between the exposure and subsequent disease: definite, probable, possible, unlikely, or unrelated. In most years, the number of cases investigated has been between 2,500 and 3,000. Excluding antimicrobials, the number of cases found after investigation to have a definite, probable, or possible relationship with pesticide exposure has ranged from 970 (in 1989) to 1,372 (in 1988). Cases involving antimicrobials rarely were reported prior to 1987. In that year, surveillance staff began reviewing workers' compensation records personally, with the specific goal of identifying antimicrobial cases. Since then, antimicrobials have been found to account for 746-813 cases annually, primarily involving splashes and squirts to the eye and inhalation of fumes or vapors. Numbers of case reports from agricultural situations have varied irregularly, driven by small numbers of episodes concerning multiple individuals. Variability in numbers of cases involving the skin has depended almost entirely on variation in numbers of field worker dermatitis. The most common situation for field worker dermatitis has been summer work in table grapes grown in the southern San Joaquin valley. In the two years since reentry intervals for the acaricide propargite were lengthened, there have been no more major clusters of field worker dermatitis. Although the cases collected by the surveillance program are predominantly occupational, because of dependence on workers' compensation for case identification, most recorded deaths are nonoccupational. Nonoccupational fatalities include suicides, mistaken ingestion of pesticides (especially if stored in food containers), and entry into structures being fumigated. Occupational deaths are less common and more varied. The circumstances of each reported occupational death are summarized above.

California↗

Extrapolation of heterocyclic amine carcinogenesis data from rodents and nonhuman primates to humans.

Twenty different heterocyclic amines have been isolated and identified from cooked foods especially beef, fish, pork and fowl. Other HCAs have also been isolated but their structure remains to be elucidated and new HCAs are likely to be identified in the future. The HCAs are highly mutagenic and all ten HCAs that have been tested for carcinogenic activity, produce tumors in mice and rats. For humans the average daily intake of HCAs is in quantities of 10-20 mg/person/day. The HCAs are procarcinogens and are activated by the cytochrome P450 system especially CYP 1A2. Rodents, monkeys and humans have the capacity to activate HCAs. Studies using hepatic microsomes demonstrated that humans have a greater capacity to activate the majority of HCAs tested than rodents or cynomolgus monkeys. Three HCAs are currently under evaluation in nonhuman primates for carcinogenic activity and one, IQ, is highly carcinogenic inducing primary hepatocellular carcinomas in the majority of cynomolgus monkeys treated. Epidemiological studies, although not definitive, are supportive of an association of HCAs intake to the etiology of human cancer. Risk assessments from animal data show a risk of HCAs to humans in the range of 10(-3) to 10(-4) which is an order of magnitude greater than compounds currently regulated by the U.S. Food and Drug Administration or the Environmental Protection Agency. Taken together evidence from mutagenicity data, activation by various species including humans, carcinogenicity in animals, human consumption data, epidemiological studies and risk assessment, supports the conclusion that HCAs are probable human carcinogens.

Amines↗

Use of Biota-Sediment Accumulation Factors to Assess Similarity of Nonionic Organic Chemical Exposure to Benthically-Coupled Organisms of Differing Trophic Mode

The U.S. Environmental Protection Agency is in the process of developing Sediment Quality Criteria (SQC) to specify the acceptable degree of risk from sediment-mediated chemical exposure for the protection of benthically-coupled organisms. In this study, potential differences in chemical exposure for benthic organisms of differing habitats or feeding types were evaluated through the use of Biota-Sediment Accumulation Factors (BSAFs). It was hypothesized that If species of different habitats have similar exposures, then the BSAF values should not be different. The BSAFs are calculated using the concentrations of chemicals in an organism (&mgr;g/g lipid) divided by the concentrations of the same chemicals in sediment (&mgr;g/gOC). Data from both freshwater and saltwater studies that met specified criteria for data quality were obtained from published papers or reports. These included three laboratory and five field studies containing 27 species and 4054 BSAF values. The BSAFs were intercompared for similarity of central tendency as grouped by chemical class (PCBs, PAHs, pesticides), individual species, and species grouped by habitat (infaunal deposit feeder, scavenger, filter feeder, and benthically-coupled fish). Plots of BSAFs grouped by class and KOW revealed that the BSAFs for the PAHs were uniformly lower (mean 0.34) than the PCB (1.03) or pesticide (1.36) classes. For the PCBs, the BSAFs for all species exhibited a KOW dependency with decreased bioaccumulation evident above and below the range of 5.99-7.27 log10 KOW. In order to optimize the detection of species/habitat differences in the BSAFs, further analyses were segregated by chemical class and excluded PCB data outside the above KOW range. These analyses revealed similar BSAF values for various species both within and among habitat groups, and indicated that the sum total of exposures from all routes is similar across species. This similarity of chemical exposure across benthic species, and the similarity of sensitivities between benthic species and species used to derive WQC FCVs supports the applicability of SQC for all benthic organisms as a group.

Journal Article↗

Risks posed by various components of hair dyes.

In this study, I calculated the risks presented by the use of several chemicals that are or were used in hair dyes and for which a good animal bioassay is available. The risks were calculated using the carcinogenic potency measure used in the National Cancer Institute bioassays concerning the exposure of rats and mice to these chemicals. The procedure used was that previously discussed by Zeise et al.; it is similar to, but logically more complete, than those normally used by Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA). The expected value of the risk for the worst dye that has now been discontinued is as high as that of smoking 6 cigarettes in a lifetime; the 95th percentile gives a risk equivalent to that of smoking 120 cigarettes in a lifetime or 2 per year. Even when the upper limits of carcinogenic potency of the untested chemicals are employed using correlations with toxicity, the estimated risk remains small.

Animals↗