Showing papers in "Critical Reviews in Toxicology in 1994"

Polychlorinated Biphenyls (PCBs): Environmental Impact, Biochemical and Toxic Responses, and Implications for Risk Assessment

Abstract: Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds ...

The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity.

Abstract: This article reviews the present state of the art regarding the toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The absorption, body distribution, and metabolism can vary greatly between species and also may depend on the congener and dose. In biota, the 2,3,7,8-substituted PCDDs and PCDFs are almost exclusively retained in all tissue types, preferably liver and fat. This selective tissue retention and bioaccumulation are caused by a reduced rate of biotransformation and subsequent elimination of congeners with chlorine substitution at the 2,3,7, and 8 positions. 2,3,7,8-Substituted PCDDs and PCDFs also have the greatest toxic and biological activity and affinity for the cytosolic arylhydrocarbon (Ah)-receptor protein. The parent compound is the causal agent for Ah-receptor-mediated toxic and biological effects, with metabolism and subsequent elimination of 2,3,7,8- substituted congeners representing a detoxification process. Congener-specific affinity of PCDDs and PCDFs for the Ah-receptor, the genetic events following receptor binding, and toxicokinetics are factors that contribute to the relative in vivo potency of an individual PCDD or PCDF in a given species. Limited human data indicate that marked species differences exist in the toxicokinetics of these compounds. Thus, human risk assessment for PCDDs and PCDFs needs to consider species-, congener-, and dose-specific toxicokinetic data. In addition, exposure to complex mixtures, including PCBs, has the potential to alter the toxicokinetics of individual compounds. These alterations in toxicokinetics may be involved in some of the nonadditive toxic or biological effects that are observed after exposure to mixtures of PCDDs or PCDFs with PCBs.

Styrene Production, Use, and Human Exposure

Abstract: Styrene is an extremely important commodity chemical used extensively in the manufacture of numerous polymers and copolymers, including polystyrene, acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile (SAN), styrene-butadiene latex, and styrene-butadiene rubber. Styrene is a component of cigarette smoke and automobile exhaust, and it may occur naturally at low levels in various types of foods. The highest potential human exposures to styrene occur in occupational settings, particularly those involving the production of large glass-reinforced polyester products such as boats, which require manual lay-up and spray-up operations. Substantially lower occupational exposures occur in styrene monomer and polymer production facilities. The general public is exposed to very low concentrations of styrene in ambient air, indoor air, food, and drinking water.

Review of the metabolic fate of styrene.

Abstract: Styrene and styrene oxide have been implicated as reproductive toxicants, neurotoxicants, or carcinogens in vivo or in vitro. The use of these chemicals in the manufacture of plastics and polymers and in the boat-building industry has raised concerns related to the risk associated with human exposure. This review describes the literature to date on the metabolic fate of styrene and styrene oxide in laboratory animals and in humans. Many studies have been conducted to assess the metabolic fate of styrene in rats, and investigations on the metabolism of styrene in humans have been of considerable interest. Limited research has been done to assess metabolism in the mouse. The metabolism of styrene to styrene oxide and further conversion to styrene glycol (via epoxide hydrolase), mandelic acid, and phenylglyoxylic acid has been given considerable attention, and is considered to be the major pathway of activation and detoxication for humans. While the hydrolysis of styrene oxide to styrene glycol historically has been the favored pathway for the rat, studies in more recent years have indicated that glutathione conjugation also is a viable and significant pathway for both the rat and the mouse. This pathway has not been established in humans. Mandelic acid and phenylglyoxylic acid have been used as urinary markers of exposure in humans exposed to styrene. Extensive investigations have been conducted on the kinetics of styrene and styrene oxide in rodents. In people, the kinetics of styrene and styrene oxide in the blood of occupationally exposed workers and volunteers have been determined. Pharmacokinetic models developed in the last decade have become increasingly complex, with the most recent physiologically based model describing the kinetics of styrene and styrene oxide. This model shows pronounced species differences in sensitivity coefficients for styrene or styrene oxide between mice, rats, and humans, where mice are the more sensitive species to the Vmax for both epoxide hydrolase and monooxygenase. This result is particularly interesting in light of the recent findings of extensive mortality and hepatotoxicity for mice exposed to relatively low levels of styrene (250 to 500 ppm), while rats and humans exhibit only nasal and eye irritations at exposure concentrations well above 500 ppm.

A Perspective on Benzene Leukemogenesis

Abstract: Although benzene is best known as a compound that causes bone marrow depression leading to aplastic anemia in animals and humans, it also induces acute myelogenous leukemia in humans The epidemiological evidence for leukemogenesis in humans is contrasted with the results of animal bioassays This review focuses on several of the problems that face those investigators attempting to unravel the mechanism of benzene-induced leukemogenesis Benzene metabolism is reviewed with the aim of suggesting metabolites that may play a role in the etiology of the disease The data relating to the formation of DNA adducts and their potential significance are analyzed The clastogenic activity of benzene is discussed both in terms of biomarkers of exposure and as a potential indication of leukemogenesis In addition to chromosome aberrations, sister chromatid exchange, and micronucleus formation, the significance of chromosomal translocations is discussed The mutagenic activity of benzene metabolites is reviewed and benzene is placed in perspective as a leukemogen with other carcinogens and the lack of leukemogenic activity by compounds of related structure is noted Finally, a pathway from exposure to benzene to eventual leukemia is discussed in terms of biochemical mechanisms, the role of cytokines and related factors, latency, and expression of leukemia

The Expression and Environmental Regulation of P450 Enzymes in Human Placenta

Abstract: The human placenta oxidizes several xenobiotics, although the spectrum of substrates and metabolic activities when compared with the liver appears somewhat restricted. Maternal cigarette smoking or PCB exposure increases the expression of CYP1A1. This induced activity is able to catalyze the activation of benzo(a)pyrene (B(a)P) into DNA-bound products, both in vitro and in vivo. Studies on adult human liver bolster the concept that CYP1A1 and -1A2 are differentially expressed in hepatic and extrahepatic tissues. Studies with cDNA probe or enzyme specific antibodies and substrates for CYP2A, -2B, -2C, -2D, and -2E gene products have yielded negative results. There are only minimal activities that can be found in substantial quantities in placentas without maternal smoking; one example is 7-ethoxycoumarin O-deethylase (ECOD). Aromatase and cholesterol side-chain cleaving P450 mRNAs, proteins, and activities are measurable in human placentas and do not seem to be affected by maternal cigarette smoking.

Transgenic Animal Models for Measuring Mutations In Vivo

Abstract: Transgenic animal models for measuring mutations provide a powerful tool for rapidly assessing tissue-specific mutations followingin vivo treatment. These models are based on the insertion into the rodent genome of theEscherichia coli lacI (lac repressor) orlacZ (β-galactosidase) genes that serve as targets for mutations. Followingin vivo treatment of animals, genomic DNA is isolated from various tissues and the target gene is packaged into λ-phage heads; the λ-phage are used to infectE. coli in order to produce plaques. Mutations in the target gene are then detected using colorimetric or selective procedures. In this review methods are discussed for producing these transgenic models, the target genes used, gene rescue techniques, sequencing of isolated mutants, and parameters that affect dosing regimens and design of studies. We also present a summary of data published to date with these systems and present our conclusions and proposed directions for future research.

The Role of Mitotic Recombination in Carcinogenesis

Abstract: Genetic recombination systems are present in all living cells and viruses and generally contribute to their hosts' flexibility with respect to changing environmental conditions. Recombination systems not only help highly developed organisms to protect themselves from microbial attack via an elaborate immune system, but conversely, recombination systems also enable microorganisms to escape from such an immune system. Recombination enzymes act with a high specificity on DNA sequences that either exhibit extended stretches of homology or contain characteristic signal sequences. However, recombination enzymes may rarely act on incorrect alternative target sequences, which may result in the formation of chromosomal deletions, inversions, translocations, or amplifications of defined DNA regions. This review describes the characteristics of several recombination systems and focuses on the implication of aberrant recombination in carcinogenesis. The consequences of mitotic recombination on the inappropriate activation of protooncogenes and on the loss of tumor suppressor genes is discussed. Cases are reported where mitotic recombination clearly has been associated with carcinogenesis in rodents as well as humans. Several test systems able to detect recombinagenic activities of chemical compounds are described.

Evidence for DNA and protein binding by styrene and styrene oxide.

Abstract: Styrene is metabolized to styrene oxide, a direct-acting mutagen and carcinogen. Styrene oxide reacts with DNA mainly at the N-7 position in guanine, but also at other sites and with other bases. Substitution occurs at both the alpha- and beta-positions of the styrene molecule. Experiments with radiolabeled styrene and styrene oxide demonstrate that both have a low level of DNA binding activity in experimental animals. 32P-Postlabeling studies have demonstrated the potential of the technique to detect styrene-DNA adducts. Styrene oxide alkylates several nucleophilic sites in proteins, particularly cysteine sulfydryl, histidine imidazole, lysine amino, aspartic, and glutamic carboxylic groups, and the N-terminal position. In experimental animals, styrene oxide treatment results in cysteine adducts in hemoglobin and albumin, valine adducts in hemoglobin, and carboxylic acid adducts in hemoglobin. The extent of alkylation is low compared with that produced by ethylene oxide. The available evidence indicates, therefore, that styrene and styrene oxide have low DNA and protein binding activities in vivo. There is preliminary evidence for the presence of DNA adducts and for adducts in hemoglobin and albumin in blood cells of styrene-exposed workers. Nevertheless, the applicability and sensitivity of DNA and protein adduct detection methods for monitoring human exposure to styrene remain to be determined.

Carcinogen Risk Assessment in the U.S. Environmental Protection Agency

Abstract: This is a narrative account of the origins and development of carcinogen risk assessment in the U.S. EPA, which pioneered the field. It began in an era of high hopes that the regulation of carcinogens in the environment would make a major reduction in the heavy public health burden of cancer. The immediate cause for the development of carcinogen risk assessment was the need to respond to heavy criticism that the EPA was not using science in an unbiased way to defend its regulation of important pesticides as carcinogens. The formulation of the initial assessment guidelines is described as well as the rationale behind the assessment procedures that were developed by the EPA's Carcinogen Assessment Group. The issue of whether the original hopes of reducing cancer has been realized is discussed. Recent developments in molecular carcinogenesis point to the possibility of a revised view of the role of environmental carcinogens at low levels of exposure from that of causing cancerde novo to an accelerati...

Risk assessment of d-limonene: an example of male rat-specific renal tumorigens.

Abstract: The naturally occurring food constituent d-limonene has been found to cause tumors at high doses only in the kidney of the male rat in association with the development of hyaline droplet nephropathy. In contrast, neither kidney tumors nor the associated nephropathy have been found in female rats or mice at much higher doses. Adult male rats produce large quantities of a specific low-molecular-weight protein in the liver, which is known as alpha 2U-globulin (alpha 2U-g). With administration of sufficient doses of d-limonene to male rats, this protein has been found to accumulate excessively in the P2 segment cells of renal proximal tubules, resulting in hyaline droplet formation as a manifestation of protein overload. Hyaline droplet accumulation is the first stage in a unique sequence of nephropathic lesions (also known as alpha 2U-g nephropathy), including granular casts in the outer medulla and linear mineralization in the papilla. The mechanism underlying protein accumulation appears to be the reversible binding of chemical to alpha 2U-g with subsequent prolongation of its half-life in the tubule cell. In the case of d-limonene, the minor metabolite d-limonene-1,2-oxide has been shown to be the primary chemical species that binds reversibly to alpha 2U-g, impeding the normal process of lysosomal proteinase degradation of alpha 2U-g. The ensuing nephropathy is associated with a sustained increase in compensatory renal tubule cell proliferation, which provides the putative mechanistic link with renal tumor formation possibly through tumor promotion of spontaneously initiated cells or enhanced spontaneous mutagenesis. This proposed mechanism has been supported by additional information, including negative genotoxicity tests for d-limonene and its oxide metabolites, experimentally verified tumor promotion, and enhanced cell proliferation primarily in P2 segment tubule cells in male F344 rats, but no such effects in the alpha 2U-g-deficient NBR rat. The mechanism of d-limonene tumor development does not appear to be possible in humans since neither the quantity nor the type of protein that binds d-limonene or d-limonene-1,2-oxide is present. The deduction that the renal tumors induced in male rats are not relevant to human carcinogenicity in the hazard evaluation step of risk assessment completes the evaluation of human risk for d-limonene. Consequently, it can be concluded that d-limonene does not pose any carcinogenic or nephrotoxic risk to humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicology of Selected Nitric Oxide-Donating Xenobiotics, with Particular Reference to Azide

Abstract: Nitric oxide (NO) has been discovered recently to be a ubiquitous, endogenous mediator, which is responsible for a variety of normal physiological functions. However, NO also has been implicated in several pathophysiological processes. For example, the pulmonary toxicity of various nitrogen oxides, including NO, found in photochemical smog has been studied for decades; endogenous NO also is associated with bleomycin-induced lung damage, as well as other adverse effects. Recently, a variety of xenobiotics have been shown to owe their biological activity in vivo to their biotransformation to NO. Thus, the therapeutic vasodilatation produced by drugs such as nitroglycerin and sodium nitroprusside is now believed to result from their release of NO, which then mimics the effects of endogenously synthesized NO. The toxic effects of NO prodrugs are, therefore, a matter of concern, especially the extent to which, if any, NO contributes to their toxicity. As reviewed here, NO does not appear to contribute importantly to the toxicity of the NO donors nitrite, hydroxylamine, or nitroprusside. However, it is by no means clear whether or not the NO generated in vivo from sodium azide contributes in a major way to its toxicity. Azide is almost as acutely toxic as cyanide, with which it shares a number of biological effects; yet, azide also has certain cardiovascular actions in common with nitrite. Unlike either cyanide or nitrite, some evidence suggests a tendency for azide to produce low-grade cumulative toxicity. In laboratory animals, azide frequently produces nonasphyxial convulsions, whereas most human deaths appear to be the result of cardiovascular collapse. Neither of these azide-induced syndromes appears to be due to the inhibition of cytochrome c oxidase. Azide is widely used as a preservative in aqueous laboratory reagents and as the propellant in automobile air bags and aircraft escape chutes. Both of these inflable systems are generally safe, and will prevent untold numbers of injuries and deaths. However, to protect workers who handle these devices and others who may come into contact with the sodium azide propellant in these systems, our rudimentary knowledge of azide toxicity needs to be expanded.

The neuroepidemiology of styrene : a critical review of representative literature

Abstract: Because exposure to styrene occurs commonly in some industries and styrene is highly lipid soluble, it is reasonable to be concerned about the possibility that styrene is neurotoxic. Styrene, like many other solvents, volatile anesthetics, and drugs, does, at certain concentrations, produce acute changes in consciousness with consequent alterations of feelings, cognition, and psychomotor functioning. Such acute actions do not imply that styrene also would produce reversible or irreversibledamage to the nervous system; the evaluation of long-term exposures to styrene also is necessary to draw conclusions about the full range of neural effects that styrene might produce. To that end, several studies of workers exposed to styrene for up to 30 years have been undertaken in factories in many parts of the world. Epidemiologists have suggested that neuropsychological deficits such as slowing of reaction time, loss of color vision, and vestibulooculomotor dysfunction are reliably induced by styrene at lev...

The role of brain-immune interactions in immunotoxicology.

Abstract: Certain xenobiotics (or the metabolites) can damage immunocompetence by directly interacting with one or more of the cells of the immune system and adversely affecting its function. It has also been proposed that xenobiotics may indirectly affect immune function by affecting other organ systems that will in turn affect immunocompetence. This review surveys evidence that supports the existence of a functional link between the brain and the immune system. In addition, we review data that support the concept that a xenobiotic-induced dysfunction in the neuroendocrine system may be associated with an immune dysfunction as well. Such chemicals do not necessarily interact directly with immunocompetent cells but would instead act to disrupt regulatory brain-immune interactions. This class of indirectly acting immunotoxic xenobiotics would not be detected in the typicalin vitro screening assays.

Review of styrene and styrene oxide long-term animal studies

Abstract: Eleven long-term toxicity studies were reviewed on styrene and five on styrene oxide in an effort to evaluate the potential carcinogenic activity of these chemicals in animals. The styrene studies included inhalation exposure (rats, mice, guinea pigs, and rabbits), intragastric gavage (rats and mice), drinking water (rats), and intraperitoneal injection (rats), while styrene oxide exposure was via intragastric gavage (rats and mice) or skin painting (mice). Each study was reviewed and evaluated for details and adequacy of design, adequacy of reported data, and interpretation. The results of this review are1. There was no convincing evidence of carcinogenic activity of styrene in animals, although many of the studies were considered inadequate.2. Styrene oxide was carcinogenic to the forestomach of both sexes of rats and mice after gavage exposure and was associated with an increase in liver neoplasms in male mice in one study. No carcinogenic activity was observed in mice after dermal exposure (sk...

Epidemiological Studies of Styrene-Exposed Populations

Abstract: The potential human carcinogenicity of styrene has been investigated mainly by epidemiological studies of occupationally exposed populations. Several cohort studies have suggested that workers exposed to styrene in the chemical industry have increased mortality from lymphatic and hematopoietic cancer. However, this finding has not been consistent and has not been reproduced in studies of reinforced plastics manufacturers, whose exposures to styrene are generally higher. The explanation for the observed associations may therefore be confounding by concomitant exposures to other chemicals such as benzene and butadiene, which are not used in the reinforced plastics industry. Despite their large size, the published studies of mortality and cancer incidence lack the statistical power to rule out an important hazard from long-term exposure to high (>50 ppm) airborne concentrations of styrene. However, they indicate that any risk of cancer from lower levels of exposure is likely to be small.

Intragenomic heterogeneity of DNA damage formation and repair: a review of cellular responses to covalent drug DNA interaction.

Abstract: Chemical DNA interaction and its processing can now be studied at the level of specific genomic regions. Such investigations have revealed important new information about the molecular biology of the cellular responses to genomic insult and especially of the repair processes. They also have demonstrated that both the formation and repair of DNA damage display patterns of intragenomic heterogeneity. Therefore, mechanistic studies should involve examination of DNA damage formation and repair in specific genomic sequences besides in the overall genome to provide clues to the way in which specific modifications of DNA or chromatin could have specific biological effects. This review primarily focuses on studies done to elucidate the nature of DNA damage induction and intragenomic processing provoked by covalent drug-DNA modification in mammalian cells. The involvement of DNA damage formation and cellular processing as critical factors for genomic injury is exemplified by studies of the novel alkylating morpholinyl anthracyclines and the bifunctional alkylating agent nitrogen mustard as a prototype agent for covalent drug DNA interaction.

Styrene: toxicity studies--what do they show?

Abstract: Styrene is efficiently metabolized to styrene oxide, which is itself readily detoxified by the same enzymes as those involved in the metabolism of various foodstuffs. Styrene oxide, like many intermediate metabolites of foodstuffs, is genotoxic and, if introduced directly into the stomachs of rodents in high doses/concentrations, gives rise to cancers of the forestomach. Exposing mice to doses of styrene high enough to overwhelm the capacity of the body to detoxify styrene oxide has been reported to increase lung tumor incidence in mice. The findings in eight epidemiological studies provide reassurance that occupational exposure to styrene is not associated with increased cancer risk. Tests for reproductive toxicity have given negative results, but effects on blood dopamine and hypothalamic and pituitary function and menstrual cycling under conditions of very high exposure have been reported. In light of all the available information, it is concluded that migration of styrene from food-wrapping materials is not a matter for toxicological concern.