A probabilistic framework for the reference dose (probabilistic RfD).

Determining the probabilistic limits for the uncertainty factors used in the derivation of the Reference Dose (RfD) is an important step toward the goal of characterizing the risk of noncarcinogenic effects from exposure to environmental pollutants. If uncertainty factors are seen, individually, as "upper bounds" on the dose-scaling factor for sources of uncertainty, then determining comparable upper bounds for combinations of uncertainty factors can be accomplished by treating uncertainty factors as distributions, which can be combined by probabilistic techniques. This paper presents a conceptual approach to probabilistic uncertainty factors based on the definition and use of RfDs by the U.S. EPA. The approach does not attempt to distinguish one uncertainty factor from another based on empirical data or biological mechanisms but rather uses a simple displaced lognormal distribution as a generic representation of all uncertainty factors. Monte Carlo analyses show that the upper bounds for combinations of this distribution can vary by factors of two to four when compared to the fixed-value uncertainty factor approach. The probabilistic approach is demonstrated in the comparison of Hazard Quotients based on RfDs with differing number of uncertainty factors.

An approach for modeling noncancer dose responses with an emphasis on uncertainty.

This paper presents an approach for characterizing the probability of adverse effects occurring in a population exposed to dose rates in excess of the Reference Dose (RfD). The approach uses a linear threshold (hockey stick) model of response and is based on the current system of uncertainty factors used in setting RfDs. The approach requires generally available toxicological estimates such as No-Observed-Adverse-Effect Levels (NOAELs) or Benchmark Doses and doses at which adverse effects are observed in 50% of the test animals (ED50s). In this approach, Monte Carlo analysis is used to characterize the uncertainty in the dose response slope based on the range and magnitude of the key sources of uncertainty in setting protective doses. The method does not require information on the shape of the dose response curve for specific chemicals, but is amenable to the inclusion of such data. The approach is applied to four compounds to produce estimates of response rates for dose rates greater than the RfD.

Uncertainty and variation in indirect exposure assessments: an analysis of exposure to tetrachlorodibenzo-p-dioxin from a beef consumption pathway.

Indirect exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other toxic materials released in incinerator emissions have been identified as a significant concern for human health. As a result, regulatory agencies and researchers have developed specific approaches for evaluating exposures from indirect pathways. This paper presents a quantitative assessment of the effect of uncertainty and variation in exposure parameters on the resulting estimates of TCDD dose rates received by individuals indirectly exposed to incinerator emissions through the consumption of home-grown beef. The assessment uses a nested Monte Carlo model that separately characterizes uncertainty and variation in dose rate estimates. Uncertainty resulting from limited data on the fate and transport of TCDD are evaluated, and variations in estimated dose rates in the exposed population that result from location-specific parameters and individuals' behaviors are characterized. The analysis indicates that lifetime average daily dose rates for individuals living within 10 km of a hypothetical incinerator range over three orders of magnitude. In contrast, the uncertainty in the dose rate distribution appears to vary by less than one order of magnitude, based on the sources of uncertainty included in this analysis. Current guidance for predicting exposures from indirect exposure pathways was found to overestimate the intakes for typical and high-end individuals.

Exposure assessment: then, now, and quantum leaps in the future.

Health risk assessments have become so widely accepted in the United States that their conclusions are a major factor in many environmental decisions. Although the risk assessment paradigm is 10 years old, the basic risk assessment process has been used by certain regulatory agencies for nearly 40 years. Each of the four components of the paradigm has undergone significant refinements, particularly during the last 5 years. A recent step in the development of the exposure assessment component can be found in the 1992 EPA Guidelines for Exposure Assessment. Rather than assuming worst-case or hypothetical maximum exposures, these guidelines are designed to lead to an accurate characterization, making use of a number of scientific advances. Many exposure parameters have become better defined, and more sensitive techniques now exist for measuring concentrations of contaminants in the environment. Statistical procedures for characterizing variability, using Monte Carlo or similar approaches, eliminate the need to select point estimates for all individual exposure parameters. These probabilistic models can more accurately characterize the full range of exposures that may potentially be encountered by a given population at a particular site, reducing the need to select highly conservative values to account for this form of uncertainty in the exposure estimate. Lastly, our awareness of the uncertainties in the exposure assessment as well as our knowledge as to how best to characterize them will almost certainly provide evaluations that will be more credible and, therein, more useful to risk managers.(ABSTRACT TRUNCATED AT 250 WORDS)

Reevaluation of dioxin bioconcentration and bioaccumulation factors for regulatory purposes.

Bioconcentration factors (BCF) or bioaccumulation factors (BAF) reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) in aquatic environments encompass a wide range of values, from less than 1000 to 189,000 l/kg. These values are based on concentrations of TCDD in various environmental media including water, sediment, or food. Under the Federal Water Pollution Control Act and its enabling regulations (40 CFR 100-140, 400-470), point source discharge limits are established so that the nominal receiving water concentration will not exceed the water quality criterion. To be consistent with this regulatory process, the water quality criterion should also be calculated using an accumulation factor that is based on a nominal water concentration. The regulatory process for developing a water quality criterion for TCDD requires the selection of a BAF that describes the relationship between the source to be regulated and the fish tissue concentration.

Pathology reevaluation of the Kociba et al. (1978) bioassay of 2,3,7,8-TCDD: implications for risk assessment.

The chronic bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) reported in 1978 by Kociba et al. has been considered to be the primary evidence supporting its carcinogenicity, and is the basis for most dioxin regulations in North America and Western Europe. Because the histopathological criteria for proliferative lesions in the rat liver have changed significantly since 1978, a reevaluation of the liver slides was conducted recently by an independent panel of pathologists. Using current National Toxicology Program criteria, their study showed, in contrast to the original findings, that about two-thirds fewer tumors were present in the livers of female Sprague-Dawley rats. The no-observed-adverse-effect level (NOAEL) for hepatocellular carcinomas was 0.01 micrograms/kg/d rather than 0.001 micrograms/kg/d, which had been reported in 1978. In light of these significant findings, a quantitative dose-response assessment of 2,3,7,8-TCDD was undertaken to predict the potential carcinogenic risks to humans. Risk-specific doses (RsDs) and cancer potency factors (CPFs) were calculated by applying the linearized multistage (LMS) model to the combined incidences of hepatocellular carcinomas and adenomas, classified in accordance with the 1990 histopathological criteria. Based on the weight of evidence regarding the mechanism of action of 2,3,7,8-TCDD, body weight rather than surface area was selected as the appropriate means for scaling rodent data to predict the human response. Using the survival-adjusted data, the RsD for a 1 in 1,000,000 (10(-6)) plausible upper bound (95%) lifetime incremental cancer risk was 370 fg/kg/d based only on the incidence of hepatocellular carcinomas, and 100 fg/kg/d when hepatocellular carcinomas and adenomas were combined. The corresponding upper-bound (95%) CPFs were 2700 and 9700 (mg/kg/d)-1, respectively. These results indicate that the carcinogenic risk to humans from exposure to 2,3,7,8-TCDD is at least 16-fold lower than previous estimates derived from the Kociba et al. (1978) bioassay.

Risk assessment of 2,3,7,8-TCDD using a biologically based cancer model: a reevaluation of the Kociba et al. bioassay using 1978 and 1990 histopathology criteria.

The Moolgavkar-Venzon-Knudson (M-V-K) two-stage model for carcinogenesis was used to estimate the risk-specific dose (RsD) based on the incidence of tumors reported by Kociba et al. (1978) for Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; dioxin). The results from the recently completed (1990) reevaluation of the Kociba et al. study, which used the current National Toxicology Program (NTP) pathology criteria, were also evaluated. Time-to-tumor information for each rat was incorporated into the analysis. Model parameters for the approximate form of the hazard function of the two-stage M-V-K model were determined by maximum likelihood estimation. This simplification was significant but necessary, because laboratory data on the intermediate cell growth rate and the transition rates have not been determined. Estimates of the RsD (10(-6) risk) (based on the original 1978 histopathology results) were 10 fg/kg/d when carcinomas and hyperplastic nodules were combined and 150 fg/kg/d when only carcinomas were considered. In contrast, using the 1990 histopathology data, the RsD (10(-6) risk) was 80 fg/kg/d when adenomas and carcinomas were combined and 25,000 fg/kg/d when only hepatocellular carcinomas were considered. Since the two-stage M-V-K model is intended to predict the occurrence of malignant tumors, the mathematically appropriate RsD is 25,000 fg/kg/d (10(-6) risk). Because the model does not account for pharmacokinetics or the possibility of other toxic effects, the appropriate RsD (10(-6) risk) for humans should be much smaller. Using the carcinoma data only, a sensitivity analysis of key parameters in the model was conducted. Results indicated that the ranges of plausible values for the RsD (10(-6) risk) for the original 1978 and the 1990 reevaluation data were 70-2600 fg/kg/d and 120-50,000 fg/kg/d, respectively. The lowest plausible RsD is, therefore, approximately 10-fold greater than the current U.S. EPA RsD (10(-6) risk) of 6.4 fg/kg/d [which is based on the linearized multistage (LMS) model]. Even though these results must be considered preliminary until some of the values for the model parameters are experimentally determined and a complete physiologically based or receptor-based model is developed, this analysis shows that nearly any plausible laboratory data on tumor progression will yield a much higher RsD than currently embraced by the U.S. EPA.

The current practice of health risk assessment: potential impact on standards for toxic air contaminants.

Since the Bhopal incident, the public has placed pressure on regulatory agencies to set community exposure limits for the dozens of chemicals that may be released by manufacturing facilities. More or less objective limits can be established for the vast majority of these chemicals through the use of risk assessment. However, each step of the risk assessment process (i.e., hazard identification, dose-response assessment, exposure assessment, and risk characterization) contains a number of pitfalls that scientists need to avoid to ensure that valid limits are established. For example, in the hazard identification step there has been little discrimination among animal carcinogens with respect to mechanism of action or the epidemiology experience. In the dose-response portion, rarely is the range of "plausible" estimated risks presented. Physiologically based pharmacokinetic (PB-PK) models should be used to understand the difference between the tissue doses and the administered dose, as well as the difference in target tissue concentrations of the toxicant between rodents and humans. Biologically-based models like the Moolgavkar-Knudson-Venzon (MKV) should be developed and used, when appropriate. The exposure assessment step can be significantly improved by using more sensitive and specific sampling and analytical methods, more accurate exposure parameters, and computer models that can account for complex environmental factors. Whenever possible, model predictions of exposure and uptake should be validated by biological monitoring of exposed persons (urine, blood, adipose) or by field measurements of plants, soil, fish, air, or water. In each portion of an assessment, the weight of evidence approach should be used to identify the most defensible value. In the risk characterization, the best estimate of the potential risk as well as the highest plausible risk should be presented. Future assessments would be much improved if quantitative uncertainty analyses were conducted. Procedures are currently available for making future assessments. By correcting some of these shortcomings in how health risk assessments have been conducted, scientists and risk managers should be better able to identify scientifically appropriate ambient air standards and emission limits.

Usefulness of low dose guanfacine, once a day, for 24-hour control of essential hypertension.

The 24-hour duration of the antihypertensive effect of guanfacine, a centrally acting alpha 2-adrenoceptor agonist administered once a day, was demonstrated in a 12-week, multicenter, double-blind, placebo-controlled study. Two hundred and forty-nine patients who remained mildly to moderately hypertensive following a 5-week period, during which they had been weaned from previous antihypertensive medications and stabilized on 25-mg chlorthalidone taken once a day, were involved. Of the 249 patients, 126 received guanfacine as a step-2 agent and 123 received placebo. Both groups were further subdivided so that blood pressure (BP) measurements were determined either 12 or 24 hours after dosing. The initial dose of guanfacine was 1 mg/day, which could be raised 1 mg at 2-week intervals to a maximum daily dose of 3 mg/day at the discretion of each investigator. The daily dose could also be lowered by 1 mg at 2-week intervals, depending on patient response. The mean 24-hour reductions with guanfacine in sitting diastolic BP (-11 mm Hg), systolic BP (-14 mm Hg) and mean arterial pressure (-12 mm Hg) were statistically significant (p less than 0.01) compared with the reductions in BP with placebo. Heart rate also decreased with guanfacine, but no clinically relevant bradycardia (less than 60 beats/min) was observed. Dry mouth (47%), constipation (16%), fatigue (12%) and drowsiness (4%) were the most frequently reported side effects. The highly acceptable side-effects profile of guanfacine was also indicated by the small percentage of patients (7%) who prematurely left the study because of adverse reactions.

Historical development of saralasin.

The research environment in which saralasin was discovered has been described, and illustrations of the rationale which contributed to its synthesis, selection for development, and eventual development have been presented. As an example, the synthesis of [Sar1, Val5, Ala8]-AII (P113, saralasin) was an attempt to make an AII antagonist which would be resistant to metabolism by aminopeptidases. Subsequent evaluation, however, indicated that the substitution of sarcosine had not only protected against aminopeptidase degradation but unexpectedly also had greatly increased the octapeptide's affinity for vascular smooth muscle receptors. Finally, the laboratory demonstration of saralasin as a potential therapeutic and diagnostic entity and the clinical confirmation of use of saralasin in hypertensive patients are reviewed.