Troyce D. Jones

Sulfur mustard as a carcinogen: Application of relative potency analysis to the chemical warfare agents H, HD, and HT

A relative potency method for assessing potential human health effects from exposures to relatively untested chemicals is presented and documented. The need for such a method in evaluating the carcinogenic potential of the chemical warfare agent sulfur mustard (agent HD) from a limited data base is specifically addressed. The best-estimate potency factor for sulfur mustard relative to benzo[a]pyrene is 1.3, with an interquartile range of 0.6 to 2.9. The method is applied to (1) the estimated fence-boundary air concentrations of mustard during operation of a proposed agent incinerator at Aberdeen Proving Ground (APG), Maryland, and (2) the current approved general population exposure level of 1 X 10(-4) mg HD/m3 and the occupational exposure level of 3 X 10(-3) mg HD/m3. Maximum estimates of excess lifetime cancer risk for individuals at sites along the APG boundary range between 3 X 10(-8) and 1 X 10(-7). Lifetime cancer risk estimates less than or equal to 10(-6) are not now regulated by the U.S. Environmental Protection Agency or the Food and Drug Administration. Maximum estimates of excess lifetime cancer risk assuming daily exposure to the approved standards during the proposed 5 years of incinerator operation are on the order of 10(-5) for the general public and 10(-4) for the worker population. These values are considered upper limit estimates.

A unifying concept for carcinogenic risk assessments

Carcinogens influence both the initiation of abnormal cells and the subsequent promotion of such cells into neoplasia. Certain other insults seem limited to the stimulation of cellular proliferation and of carcinogenic potentiation. Common examples include surgical, mechanical, chemical, and temperature wounding of tissue followed by healing. In addition, certain hyperplastic growth induced by some chemicals may also enhance tumorigenesis. We propose that the quantification of carcinogenic potentiation may derive from a common-index-quantity estimated according to enhanced cell proliferation resulting from cytotoxicity or toxic hyperplasia induced by a specific exposure. At this time, it is not possible to define, in a restrictive sense, the molecular events which are critical to potentiation but the processes of cell proliferation resulting from cytotoxicity/hyperplasia seem to serve as indices which contain the necessary (and perhaps several secondary) biological responses. The unique advantage is that cell-culture, animal, and human-level studies can be used to evaluate certain parameters of the mathematical model for an untested treatment protocol or chemical insult suspected to be a cofactor in tumorigenesis. The main thrust of this paper is to propose that tumorigenesis should be studied in terms of cellular-population kinetics in response to a biological challenge rather than according to chemical or energetic parameters of that challenge. This approach leads to mathematical equations which can serve as a unifying concept for carcinogenic risk assessments. Sample results, to illustrate the utility of this model, are given for polynuclear aromatic hydrocarbons, trace metals, ionizing radiations, CO, NO, SO2, O3, and NO2. Treatment, here, is for acute exposure conditions, but because the model is mechanistic, other exposure protocols can be addressed by simply adjusting some of the mathematical parameters according to factors estimated from a relative potency comparison of in vitro and in vivo studies best suited to the particular application of interest.

Permissible Concentrations of Chemicals in Air and Water Derived From Rtecs Entries: a "Rash" Chemical Scoring System

Many chemicals are of concern to human health, but only a few have epidemiologically derived risk estimates. About 45,000 chemicals are listed in RTECS, most of which have had some testing in subhuman models. RTECS entries range from cellular effects through organoleptic damage to lethality, with many pathological endpoints listed, including mutagenic changes, irritation, teratogenesis, cancer, mortality, etc. However, it is difficult to extend any biological test results to human risk assessments. If the results are extended, the degree of validity is highly uncertain. This paper describes a logical basis for using the entire complex spectrum of test results to evaluate the overall toxicological potency of a chemical to be assayed (i.e., an interviewing chemical) and describes how to derive tentative, permissible concentrations in air and water for any particular chemical for which no regulatory guidance exists. This approach has been tested for 16 reference chemicals discussed in NIOSH Criteria Documents, EPA-CAG reports, etc. The evaluations are uncomplicated, but occasionally it is difficult to match RTECS entries for two different chemicals. Difficult comparisons may require some familiarity with experimental design and the toxicological literature. One important product of this novel approach is that a distribution or array of potency values is obtained for any chemical evaluated. This distribution reflects many uncertainties stemming from low statistical power, experimental design, pharmacological processes, interspecies variability, dose rate, biological effect monitored, route of treatment, etc. The array of relative values for a particular chemical reflects many different biological and physical conditions. The distribution of the array helps to index a composite toxicological profile for many different biological effects resulting from numerous treatment protocols. To minimize the effect of extreme sensitivity of certain (perhaps novel) biological test models, possible errors in the RTECS database, and possible human pharmacological insensitivity to a particular chemical and/or a particular route of administration, we consider the interquartile range (i.e., the central 50%) of the array of relative potency values between two chemicals being compared as a practical measure of uncertainty. Thus, the range in response derived from variability in relative potency should be useful in addressing the range of response in man as estimated from extrapolations of test data.

Ranking of carcinogenic potency using a relative potency approach

Protocols for long-term carcinogen bioassays have become highly refined. The ability to interpret these bioassay results beyond the experimental setting, however, has not improved commensurately. As a consequence, society is still faced with the fact that data derived in these bioassays reflect highly specific experimental conditions which are vastly different from environmental exposures of the freely roaming, outbred human. The scientific community has responded with a “collective wisdom” approach by using expert committees to interpret bioassay evidence. This committee approach is believed to be successful in protecting human health, but the list of suspected carcinogens is growing faster than the expert committees can respond.We have developed a relative potency framework for ranking the hazards represented by potential human carcinogens. The results demonstrate a rank ordering of a variety of compounds which is independent of the reference compound used to standardize the information. The philosophic basis of the approach may facilitate expert risk assessment systems development because it: (1) complements and supports “expert committee” data selection; (2) has a simple set of rules and does not require mathematical modeling; (3) requires no special situation judgments; and (4) is suitable for use with electronic data bases.

Toxicological potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin relative to 100 other compounds: A relative potency analysis of in vitro and in vivo test data

A common definition of relative potency is the dose of a reference compound required to cause a particular incidence of a specific toxic response divided by the dose of a test compound needed to cause an equal incidence of that same effect. In this simple manner, toxicological assessments for a chemical of concern can be made in terms of another compound about which much is known from a human health perspective. Relative potency factors were used to compare 2,3,7,8-tetrachlorodibenzo-p-dioxin CAS # 1746-01-6 (TCDD) with 100 other compounds both individually and collectively. All results were standardized to a common scale that spanned many orders of magnitude and was indexed to an arbitrary potency of unity for benzo(a)pyrene [B(a)P]. From comparisons between 2,771 pairs of bioassay results (i.e., matched experimental design conditions) for TCDD compared with the 100 other compounds, it was found that TCDD is about 600 times as toxic as B(a)P (interquartile range of 130 to 1,900). The distribution of relative potency values is fitted accurately with a log-normal distribution function having an untransformed mean of 550 and an untransformed slope (i.e., the inverse of the standard deviation of the distribution) of 140. These factors combined with (a) a reference lifetime carcinogenic risk level of 1/100,000 and (b) a universal, potency-dependent risk coefficient (estimated from the collection of epidemiologically-based carcinogens) yielded estimates that equally toxic concentrations for TCDD should be in the range of 13 pg/m3 and 7 pg/L in air and water, respectively.

Protection of human health from mixtures of radionuclides and chemicals in drinking water

This study was undertaken to develop a common scale for evaluating health risks from contaminated drinking water. For different agents, many unrealistic models of risk have been used. By intent, regulatory toxicology depends on “data-sparse, model-intensive” analogies from exotic animal genetics and novel exposures (NCRP 1989). The question is, does a risk evaluation so derived have any predictive validity? Absence of data prevents answer because regulatory toxicology rationalizes in step-by-step logic, which we callabsolute (i.e., predicts cases of disease in a population). Absolute models ensure safety, but do so at the cost of realism. In contrast, we makerelative comparisons in the manner of horsepower or RBE from radiation biology. All pollutants are assumed to contribute to toxic injury. Next, relative potencies are linked to the most credible standards. Thus, experience is transferred from well-studied chemicals to the new chemical by “data-intensive, model-sparse” methods. This logos provides much relative precision. Then, pollutants are compared with: (1) common foodstuffs, (2) ambient radiation background, or (3) utility-pure drinking water. Finally, an assessment is made for a waste disposal area.

Biotesting wastewater for hazard evaluation

Abstract Evaluation of the potential hazard of treated water can be performed in two basic ways: chemical identification followed by chemical-by-chemical hazard summation or by means of biotesting the water as if the contaminants were a single compound. Current practice is somewhere in between. For the most part, the use of bioassays is limited to a single test system, and the results are usually interpreted as either positive or negative. That is, binary information is the usual result of a bioassay evaluation. Our work over the past decade has facilitated the development of an alternative approach to interpreting bioassay results. The key element in our approach is the use of relative comparisons. Relative comparisons between responses of a given test system using wastewater and a well-known agent allow a graded response for each different bioassay. By using a battery of different bioassay systems, each with different mechanisms of toxicity, we are able to characterize the composite toxicological response to a wastewater sample with respect to a well-studied “reference” chemical. The value of this approach is that, if the use of the reference chemical has acceptable risk to the majority of the population or at least a known human risk, the wastewater can be evaluated with respect to that factor. We use water chlorination as a “reference” material in this report to illustrate the concept.

Relative potency estimates of acceptable residues and reentry intervals after nerve agent release

In the event of an unplanned release of a chemical warfare agent during any stage of the Chemical Stockpile Disposal Program, the potential exists for off-post contamination of drinking water, forage crops, grains, garden produce, and livestock. The more persistent agents, such as the organophosphate nerve agent VX, pose the greatest human health concern for reentry. A relative potency approach comparing the toxicity of VX to organophosphate insecticide analogues is developed and used to estimate allowable residues for VX in agricultural products and reentry intervals for public access to contaminated areas. Analysis of mammalian LD50 data by all exposure routes indicates that VX is 10(3) to 10(4) times more toxic than most commercially available organophosphate insecticides. Thus, allowable residues of VX could be considered at concentration levels 10(3) to 10(4) lower than those established for certain insecticides by the U.S. EPA. Evaluation of reentry intervals developed for these organophosphate analogues indicate that, if environmental monitoring cannot reliably demonstrate acceptable levels of VX, restricted access to suspect or contaminated areas may be on the order of weeks to months following agent release. Planning for relocation, mass care centers, and quarantine should take this time period into account.

Use of bioassays in assessing health hazards from complex mixtures: A RASH analysis

The Finney harmonic mean model for joint toxicity of ingredients in mixtures can be used to estimate the toxicity of the neat compound if each component can be substituted in potency-adjusted-doses for any of the other components. Chemical analysis of constituent substances and their associated concentrations and relative toxicological potency values (computed according to the RApid Screening of Hazard (RASH) method) were used to compare the toxicities as predicted from ingredients of cigarette smoke, PAHs in diesel exhaust, asphalt, coal tar, pitch, and creosote with the measured toxicities of the corresponding neat mixtures. Accuracy for cigarette smoke condensate, coal tar, pitch, and creosote were within a factor of three based on the PAH fraction; asphalt was within a factor of 18; but the PAH fraction of diesel particulate was again found to be inadequate to describe the composite toxicity of diesel emissions.

On the use of Relative Toxicity for Risk Estimation

Health effects assessment uses epidemiological, toxicological, and basic biological, biochemical, and biophysical data to estimate effects in humans to exposures of interest, or to rank a set of materials according to estimated human effects. Such methodology involves a number of very complex issues and must include estimates of: a human dose response function, the uncertainty in the estimated effects, the most probable range of risk as well as the upper limit risk, the predictive power of biological test systems used, comparative risks from other materials or sources, and data gaps, priorities, and research needs. A method has been developed based upon relative toxicological potency which incorporates these features.