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J Doull

Publications and source records attributed to J Doull.

At least 19 recordsLinked to original sources
PubMed2001

The role of time as a quantifiable variable of toxicity and the experimental conditions when Haber's c x t product can be observed: implications for therapeutics.

One hundred years ago, Warren established for the first time a quantitative link between dose and time while studying the toxicity of sodium chloride in Daphnia magna (Straus). During this century, many toxicologists in different contexts returned to this idea, which has become known as Haber's Rule of inhalation toxicology. Most attempts to explore this relationship ended in frustration because of the observed deviations from it, which were unfortunately called exceptions. Thus, toxicologists concentrated on the quantitative relationship between dose and effect under mostly isotemporal conditions, while time was assigned such arbitrary, semiquantitative designations as acute, subacute, subchronic, and chronic. Time itself as a quantifiable variable of toxicity was seldom studied and when it was examined, it was often not done under isodosic (steady-state) conditions. A recent analysis of time as a variable of toxicity indicated the existence of at least three independent time scales (toxicokinetic, toxicodynamic, exposure frequency/duration) in toxicological studies, which interact with dose and effect to yield the enormous complexity known to every toxicologist. Based on prototypical examples when toxicokinetic (dioxins, chloroacetic acid), toxicodynamic (nitrosamines, soman, sarin, tabun), exposure frequency (methylene chloride), or other experimental design-related conditions (HgCl(2), CdCl(2)) represent the critical time scale, the general validity of the c x t = k concept will be discussed as a starting point for a theory of toxicology. As endpoints of toxicity, (delayed) acute toxicity, blood dyscrasias, and cancer will be used to illustrate the critical conditions needed to demonstrate the validity of this theory. The relevance of this theory to the pharmacologic action of chemicals and its implication for the therapeutic index are also discussed.

Acetates↗
PubMed2000

Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase.

Toxicity and other relevant data for 30 organophosphate pesticides were evaluated to suggest inhalation occupational exposure limits (OELs), and to support development of a risk assessment strategy for organophosphates in general. Specifically, the value of relative potency analysis and the predictability of inhalation OELs by acute toxicity measures and by repeated oral exposure NOELs was assessed. Suggested OELs are based on the prevention of red blood cell (RBC) acetylcholinesterase (AChE) inhibition and are derived using a weight-of-evidence risk assessment approach. Suggested OEL values range from 0.002 to 2 mg/m(3), and in most cases, are less than current permissible exposure levels (PELs) or threshold limit values(R) (TLVs(R)). The available data indicate that experimental data for most organophosphates evaluated are limited; most organophosphates are equally potent RBC AChE inhibitors in different mammalian species; NOELs from repeated exposure studies of variable duration are usually equivalent; and, no particular grouping based on organophosphate structure is consistently more potent than another. Further, relative potency analyses have limited usefulness in the risk assessment of organophosphates. The data also indicated that equivalent relative potency relationships do not exist across either exposure duration (acute vs. repeated) or exposure route (oral vs. inhalation). Consideration of all variable duration and exposure route studies are therefore usually desirable in the development of an OEL, especially when data are limited. Also, neither acute measures of toxicity nor repeated oral exposure NOELs are predictive of weight-of-evidence based inhalation OELs. These deviations from what is expected based on the common mechanism of action for organophosphates across exposure duration and route - AChE inhibition - is likely due to the lack of synchrony between the timing of target tissue effective dose and the experimental observation of equivalent response. Thus, comprehensive interpretation of all toxicity data in the context of available toxicokinetic, toxicodynamic and exposure information for each individual organophosphate in a weight-of-evidence based risk assessment is desirable when deriving inhalation OELs.

Animals↗
PubMed2000

Dose and time as variables of toxicity.

Recognizing that if there is no exposure, there is no toxicity leads us to the conclusion that if there is exposure, toxicity can ensue when exposure exceeds a certain dose and/or time and that it will be dependent on toxicokinetics and toxicodynamics. Analysis of the fundamental description of toxicity (dT/dE=dT/dDxdD/dKxdK/dE, where T stands for toxicity, D for toxicodynamics, K for toxicokinetics and E for exposure) yields the recognition of three independent time scales, the first being an intrinsic property of a given compound (what does the chemical do to the organism), which is the dynamic time scale. The second time scale is an intrinsic property of a the organism (what does the organism do to the chemical), which represents the kinetic time scale. The frequency of exposure denotes the third time scale, which is independent of the dynamic and kinetic time scales. Frequency of exposure depends on the experimental design or on nature, but not on the organism or substance. A liminal condition occurs when the frequency becomes so high that it is indistinguishable from continuous exposure. Continuous exposure forces the two other time scales to become synchronized thereby reducing complexity to three variables: dose, effect and one time scale. Keeping one of those variables constant allows for the study of the other two variables reproducibly under isoeffective or isodosic or isotemporal conditions. However, any departure from continuous exposure will introduce the full complexity of four independent variables (dose and kinetic, dynamic and frequency time scales) impacting on the effect (dependent variable) at the same time. The examples discussed in this paper demonstrate how nature in the form of long half-lives provides liminal conditions when either kinetic or dynamic half lives force synchronization of all three time scales. However, for compounds having very short dynamic or kinetic half-lives, only continuous exposure will provide a synchronized time scale. A decision tree-type approach is being used to illustrate how to reduce the enormous complexity generated by five variables (dose, effect and up to three time scales) in toxicology to manageable proportions by identifying and modeling the rate-determining (-limiting) step(s) in the manifestation of toxicity.

Algorithms↗
PubMed1999

A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines.

The current United States Environmental Protection Agency (EPA) classification of di(2-ethylhexyl)phthalate (DEHP) as a B2 "probable human" carcinogen is based on outdated information. New toxicology data and a considerable amount of new mechanistic evidence were used to reconsider the cancer classification of DEHP under EPA's proposed new cancer risk assessment guidelines. The total weight-of-evidence clearly indicates that DEHP is not genotoxic. In vivo administration of DEHP to rats and mice results in peroxisome proliferation in the liver, and there is strong evidence and scientific consensus that, in rodents, peroxisome proliferation is directly associated with the onset of liver cancer. Peroxisome proliferation is a transcription-mediated process that involves activation by the peroxisome proliferator of a nuclear receptor in rodent liver called the peroxisome proliferator-activated receptor (PPARalpha). The critical role of PPARalpha in peroxisomal proliferation and carcinogenicity in mice is clearly established by the lack of either response in mice genetically modified to remove the PPARalpha. Several mechanisms have been proposed to explain how, in rodents, peroxisome proliferation can lead to the formation of hepatocellular tumors. The general consensus of scientific opinion is that PPARalpha-induced mitogenesis and cell proliferation are probably the major mechanisms responsible for peroxisome proliferator-induced hepatocarcinogenesis in rodents. Oxidative stress appears to play a significant role in this increased cell proliferation. It triggers the release of TNFalpha by Kupffer cells, which in turn acts as a potent mitogen in hepatocytes. Rats and mice are uniquely responsive to the morphological, biochemical, and chronic carcinogenic effects of peroxisome proliferators, while guinea pigs, dogs, nonhuman primates, and humans are essentially nonresponsive or refractory; Syrian hamsters exhibit intermediate responsiveness. These differences are explained, in part, by marked interspecies variations in the expression of PPARalpha, with levels of expression in humans being only 1-10% of the levels found in rat and mouse liver. Recent studies of DEHP clearly indicate a nonlinear dose-response curve that strongly suggests the existence of a dose threshold below which tumors in rodents are not induced. Thus, the hepatocarcinogenic effects of DEHP in rodents result directly from the receptor-mediated, threshold-based mechanism of peroxisome proliferation, a well-understood process associated uniquely with rodents. Since humans are quite refractory to peroxisomal proliferation, even following exposure to potent proliferators such as hypolipidemic drugs, it is concluded that the hepatocarcinogenic response of rodents to DEHP is not relevant to human cancer risk at any anticipated exposure level. DEHP should be classified an unlikely human carcinogen with a margin of exposure (MOE) approach to risk assessment. The most appropriate and conservative point of reference for assessing MOEs should be 20 mg/kg/day, which is the mouse NOEL for peroxisome proliferation and increased liver weight. Exposure of the general human population to DEHP is approximately 30 microg/kg body wt/day, the major source being from residues in food. Higher exposures occur occupationally [up to about 700 microg/kg body wt/day (mainly by inhalation) based on current workplace standards] and through use of certain medical devices [e.g., up to 457 microg/kg body wt/day for hemodialysis patients (intravenous)], although these have little relevance because the routes of exposure bypass critical activation enzymes in the gastrointestinal tract.

Animals↗
PubMed1999

The FEMA GRAS assessment of trans-anethole used as a flavouring substance. Flavour and Extract Manufacturer's Association.

This publication is the fourth in a series of safety evaluations performed by the Expert Panel of the Flavour and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of trans-anethole (i.e. 4-methoxypropenylbenzene) as a flavouring substance is critically evaluated by the FEMA Expert Panel. The evaluation uses a mechanism-based approach in which production of the hepatotoxic metabolite anethole epoxide (AE) is used to interpret the pathological changes observed in different species and sexes of laboratory rodents in chronic and subchronic dietary studies. Female Sprague Dawley rats metabolize more trans-anethole to AE than mice or humans and, therefore, are the most conservative model for evaluating the potential for AE-induced hepatotoxicity in humans exposed to trans-anethole from use as a flavouring substance. At low levels of exposure, trans-anethole is efficiently detoxicated in rodents and humans primarily by O-demethylation and omega-oxidation, respectively, while epoxidation is only a minor pathway. At high dose levels in rats, particularly females, a metabolic shift occurs resulting in increased epoxidation and formation of AE. Lower activity of the "fast" acting detoxication enzyme epoxide hydrolase in the female is associated with more pronounced hepatotoxicity compared to that in the male. The continuous intake of high dose levels of trans-anethole (i.e. cumulative exposure) has been shown in dietary studies to induce a continuum of cytotoxicity, cell necrosis and cell proliferation. In chronic dietary studies in rats, hepatotoxicity was observed when the estimated daily hepatic production of AE exceeded 30 mg AE/kg body weight. In female rats, chronic hepatotoxicity and a low incidence of liver tumours were reported at a dietary intake of 550 mg trans-anethole/kg body weight/day. Under these conditions, daily hepatic production of AE exceeded 120 mg/kg body weight. Additionally, neither trans-anethole nor AE show any evidence of genotoxicity. Therefore, the weight of evidence supports the conclusion that hepatocarcinogenic effects in the female rat occur via a non-genotoxic mechanism and are secondary to hepatotoxicity caused by continuous exposure to high hepatocellular concentrations of AE. trans-Anethole was reaffirmed as GRAS (GRASr) based on (1) its low level of flavour intake (54 microg/kg body weight/day); (2) its metabolic detoxication pathway in humans at levels of exposure from use as a flavouring substance; (3) the lack of mutagenic or genotoxic potential; (4) the NOAEL of 120 mg trans-anethole/kg body weight/day in the female rat reported in a 2 + -year study which produces a level of AE (i.e. 22 mg AE/kg body weight/day) at least 10,000 times the level (0.002 mg AE/kg body weight day) produced from the intake of trans-anethole from use as a flavouring substance; and (5) the conclusion that a slight increase in the incidence of hepatocellular tumours in the high dose group (550 mg trans-anethole/kg body weight/day) of female rats was the only significant neoplastic finding in a 2+ -year dietary study. This finding is concluded to be secondary to hepatotoxicity induced by high hepatocellular concentrations of AE generated under conditions of the study. Because trans-anethole undergoes efficient metabolic detoxication in humans at low levels of exposure, the neoplastic effects in rats associated with dose-dependent hepatotoxicity are not indicative of any significant risk to human health from the use of trans-anethole as a flavouring substance.

Allylbenzene Derivatives↗
PubMed1997

The FEMA GRAS assessment of furfural used as a flavour ingredient. Flavor and Extract Manufacturers' Association.

The Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA) has assessed the safety of furfural for its continued use as a flavour ingredient. The safety assessment takes into account the current scientific information on exposure, metabolism, pharmacokinetics, toxicology, carcinogenicity and genotoxicity. Furfural was reaffirmed as GRAS (GRASr) as a flavour ingredient under conditions of intended use based on: (1) its mode of metabolic detoxication in humans; (2) its low level of flavour use compared with higher intake levels as a naturally occurring component of food; (3) the safety factor calculated from results of subchronic and chronic studies, (4) the lack of reactivity with DNA; and (5) the conclusion that the only statistically significant finding in the 2-year NTP bioassays, an increased incidence of hepatocellular adenomas and carcinomas in the high-dose group of male mice, was secondary to pronounced hepatotoxicity. Taken together, these data do not indicate any risk to human health under conditions of use as a flavour ingredient. This evidence of safety is supported by the occurrence of furfural as a natural component of traditional foods, at concentrations in the diet resulting in a 'natural intake' that is at least 100 times higher than the intake of furfural from use as a flavour ingredient.

Adenoma, Liver Cell↗
PubMed1996

Specificity and dosimetry of toxicologic responses.

Toxicology has two goals. The first is to identify and characterize the adverse effects that can be produced in biological systems by exposure to chemicals and the second is to use this information to predict the type and severity of responses in other species and exposure situations. The tools that the toxicologist uses to detect and describe the adverse effects of chemical exposure include the traditional acute, subchronic, and chronic studies in animals plus a variety of special studies designed to demonstrate specific organ damage, reproductive and teratogenic effects, neurotoxicity, immunotoxicity, genotoxicity, and other responses. These are often supplemented with studies of the kinetics and the mechanism of action and more recently with studies designed to elucidate the molecular basis for cancer and other effects. Theses studies together with the information on exposure provide the basis for subsequent toxicologic predictions. Although general effects such as weight loss and mortality are included in toxicity protocols, most of the toxicology tests are related to specific end-organ toxicity or to mechanism or behavioral studies. We do not have animal protocols to study individually the subjective symptoms described for multiple chemical sensitivity, such as depression, fatigue, headache, and memory loss, and our tests lack sufficient specificity to evaluate a syndrome which is composed primarily of such symptoms. Since all chemicals can produce adverse effects under some conditions of exposure, toxicologic predictions are most useful when they specify both the type of adverse effect anticipated and the dose required to produce the effect. Multiple chemical sensitivity does not appear to consistently involve specific chemicals or specific adverse effects and the effects observed are reported to lack evidence of a threshold and to occur at extremely low levels. It is difficult to include these parameters in any reasonable toxicologic prediction relating cause and response in multiple chemical sensitivity or similar conditions.

Environmental Illness↗
PubMed1996

The FEMA GRAS assessment of alicyclic substances used as flavour ingredients.

For over 35 years, an independent panel of expert scientists has served as the primary body for evaluating the safety of flavour ingredients. This group, the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA), has achieved international recognition from the flavour industry, government regulatory bodies including the Food and Drug Administration, and the toxicology community for its unique contributions. To date, the Expert Panel has evaluated the safety of more than 1700 flavour ingredients and determined the vast majority to be "generally recognized as safe" (GRAS). Elements that are fundamental to the safety evaluation of flavour ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavour ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. The elements of the GRAS assessment program as they have been applied by the Expert Panel to the group of 119 alicyclic substances used as flavour ingredients, and the relevant scientific data which provide the basis for the GRAS status of these substances, are described herein.

Animals↗
PubMed1996

Is it safe?

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Dose-Response Relationship, Drug↗
PubMed1993

Relative potency of chlorinated dibenzo-p-dioxins (CDDs) in acute, subchronic and chronic (carcinogenicity) toxicity studies: implications for risk assessment of chemical mixtures.

This paper shows that the relative toxic potency of four chlorinated dibenzo-p-dioxins (CDDs) is similar in two species with different sensitivities (guinea pig, Sprague-Dawley rat). More importantly, it also demonstrates that the relative toxic potencies of these homologues are very similar for acute, subchronic and chronic dosing in the same species (rat). Furthermore, examination of different endpoints of toxicity (mortality, porphyria, carcinogenicity) suggests that the dose-responses for these diverse end-points after acute, subchronic, and chronic administration are very similar if not identical for tetra-CDD. Based on toxicokinetic and toxicodynamic considerations, a new, possibly generalizable rule (average tissue concentration x time = toxicity) is derived for CDDs. Implicit in the relative potency arguments of CDDs is the requirement of a practical threshold dose for all endpoints of toxicity including cancer.

Administration, Oral↗
PubMed1993

Designing a biological monitoring program to assess community exposure to chromium: conclusions of an expert panel.

The possible benefits of biological monitoring of large groups of people potentially exposed to environmental contaminants has become an area of much interest in recent years. Because chromite-ore processing residue has been found in some soils in northern New Jersey, urinary chromium monitoring of people in the community was evaluated as a potentially useful tool. In an attempt to identify those who could be exposed and to quantify the magnitude of exposure to the chromium in these soils, the New Jersey Department of Health (NJDOH) initiated a public health screening project. In 1992, the NJDOH proposed to evaluate over 4000 people who lived or worked near these sites. Volunteers were administered a questionnaire and were given a limited physical examination, and a single spot urine sample was collected. Because of the difficulties in using urinary chromium to assess low-level exposure and the potential implications of any regulatory decisions that could be based on the results of this project, a panel of experts was convened to evaluate the protocol. The panel consisted of five scientists and physicians with expertise in toxicology, dermatology, epidemiology, biological monitoring, and analytical chemistry. Like a World Health Organization group, the panel concluded that although urine biomonitoring can be useful in evaluating high levels of exposure to chromium, it is not reliable for assessing low-level exposure similar to that which may have occurred in northern New Jersey. The panel also noted that when urinary biomonitoring is to be used to assess the public's possible exposure, a large number of precautions must be taken to ensure the accuracy and usefulness of the results. The single most important recommendation was to collect a second, and perhaps a third, spot urine (or 24-h urine) sample before concluding that a person may be routinely overexposed. These suggestions are applicable to designing a biomonitoring program for nearly any environmental contaminant to which a community may be exposed. A review of scientific literature associated with biological monitoring of chromium is provided.

Absorption↗
PubMed1992

Global estimates of acute pesticide morbidity and mortality.

Mathematical models have projected increasing numbers of pesticide poisoning throughout the world, rising from 500,000 cases/yr in 1972 to 25,000,000 cases/yr in a 1990 estimate. Among 148 outbreaks (excluding Bhopal and three probable epidemics of pesticide-related suicide) reported between 1951-90, the known number of cases was 24,731 with 1065 deaths (4.3% case fatality); these are probably underestimates. Among the known outbreaks, the most commonly identified agents were organophosphates (58), carbamates (23), chlorinated hydrocarbons (23), and organic mercurials (11). Food was the most common vehicle of exposure in these epidemics (83 outbreaks), followed by skin contact (26), multiple types of exposure (22), and respiratory exposure (16). Two countries, the United States and Thailand, accounted for more than half the reports. Both the mathematical models and the outbreak investigations support the need for continuing investigation and improved surveillance throughout the world.

Accidents↗
PubMed1992

Alcohol and cancer.

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Alcohol Drinking↗