Showing papers in "Critical Reviews in Toxicology in 1990"

Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs).

Abstract: Halogenated aromatic compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and diphenylethers (PCDEs), are industrial compounds or byproducts which have been widely identified in the environment and in chemical-waste dumpsites. Halogenated aromatics are invariably present in diverse analytes as highly complex mixtures of isomers and congeners and this complicates the hazard and risk assessment of these compounds. Several studies have confirmed the common receptor-mediated mechanism of action of toxic halogenated aromatics and this has resulted in the development of structure-activity relationships for this class of chemicals. The most toxic halogenated aromatic is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and based on in vivo and in vitro studies the relative toxicities of individual halogenated aromatics have been determined relative to TCDD (i.e., toxic equivalents). The derived toxic equivalents can be used for hazard and risk assessment of halogenated aromatic mixtures; moreover, for more complex mixtures containing congeners for which no standards are available (e.g., bromo/chloro mixtures), several in vitro or in vivo assays can be utilized for hazard or risk assessment.

Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Abstract: Neuroexcitatory symptoms of acute poisoning of vertebrates by pyrethroids are related to the ability of these insecticides to modify electrical activity in various parts of the nervous system. Repetitive nerve activity, particularly in the sensory nervous system, membrane depolarization, and enhanced neurotransmitter release, eventually followed by block of excitation, result from a prolongation of the sodium current during membrane excitation. This effect is caused by a stereoselective and structure-related interaction with voltage-dependent sodium channels, the primary target site of the pyrethroids. Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed in surviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage is not observed. Occupational exposure to pyrethroids frequently leads to paresthesia and respiratory irritation, which are probably due to repetitive firing of sensory nerve endings. Massive exposure may lead to severe human poisoning symptoms, which are generally treated well by symptomatic and supportive measures.

Carcinogenicity of polyhalogenated biphenyls: PCBs and PBBs.

Abstract: Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physical/chemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiation/promotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development.

Formaldehyde Toxicity—New Understanding

Abstract: (1990). Formaldehyde Toxicity—New Understanding. Critical Reviews in Toxicology: Vol. 20, No. 6, pp. 397-426.

Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a review.

Abstract: This review evaluates the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans. The primary emphasis is on mainstream smoke ...

An assessment of the toxicological properties of pyrethroids and their neurotoxicity

Abstract: 1. Most pyrethroids can be divided into two classes on the basis of differences in the signs of toxicity (T- orCS-syndromes). Since these syndromes also correspond to particular aspects of their chemical structure and since the order of appearance of the signs of poisoning is the same in each class, it is concluded that these syndromes originate from a single primary action of the pyrethroid.2. Pyrethroids cause morphological changes in peripheral nerves of rats when given in high doses. The production of these minor lesions are correlated with a dose of the pyrethroid that causes death in some of the treated rats. Lower doses do not cause these effects. Therefore, the morphological changes are produced as a secondary consequence of the primary action of pyrethroids and are not due to a different form of toxicity.3. Pyrethroids have been shown to cause functional changes (behavioral) in rats shown as a deficit in performance on an inclined plane. Increases in peripheral nerves of β-glucuronidase a...

The Toxicity of Inhaled Methanol Vapors

Abstract: Methanol could become a major automotive fuel in the U.S., and its use may result in increased exposure of the public to methanol vapor. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures. Acute methanol toxicity evolves in a well-understood pattern and consists of an uncompensated metabolic acidosis with superimposed toxicity to the visual system. The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. In short, the toxic syndrome sets in if formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at the anticipated levels of exposure to automotive methanol vapor.

The health risks of saccharin revisited.

Abstract: Almost from its discovery in 1879, the use of saccharin as an artificial, non-nutritive sweetener has been the center of several controversies regarding potential toxic effects, most recently focusing on the urinary bladder carcinogenicity of sodium saccharin in rats when fed at high doses in two-generation studies. No carcinogenic effect has been observed in mice, hamsters, or monkeys, and numerous epidemiological studies provide no clear or consistent evidence to support the assertion that sodium saccharin increases the risk of bladder cancer in the human population. Mechanism of action studies in the one susceptible species, the rat, continue to provide information useful in assessing potential risk to the human from saccharin consumption. Unlike typical carcinogens which interact with DNA, sodium saccharin is not genotoxic, but leads to an increase in cell proliferation of the urothelium, the only target tissue. It also appears that the effect of saccharin is modified by the salt form in which it is administered, despite equivalent concentrations of saccharin in the urine. The chemical form of saccharin in the urine is unaffected, and there is no evidence for a specific cell receptor for the saccharin molecule. Changes in several urinary parameters, such as pH, sodium, protein, silicates, volume, and others, appear to influence the reaction of the urothelium to sodium saccharin administration. Silicon-containing precipitate and/or crystals appear to be generated in the urine under specific circumstances, acting as microabrasive, cytotoxic material. Using a mathematical model of carcinogenesis, which encompasses the temporal dynamics and complexity of the process at a cellular level, including spontaneous genetic transitions, it has been shown that the effects of sodium saccharin can be explained entirely in terms of its non-genotoxic influence on cell proliferation. In interpreting these analytical studies in the human context, particularly as they pertain to the urinary milieu which appears to be pivotal in the effect of sodium saccharin, we are led to the conclusion that there is a threshold effect in male rats and that an effect on the human urothelium is unlikely at even the highest levels of human consumption.

Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions.

Abstract: This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium and pH in anoxic and toxic injury

Abstract: The critical events that lead to the transition from reversible to irreversible injury remain unclear Studies are reviewed that have suggested that a rise in cytosolic free Ca2+ initiates plasma membrane bleb formation and a sequence of events that leads ultimately to cell death In recent studies, we have measured changes in cytosolic free Ca2+, mitochondrial membrane potential, cytosolic pH, and cell surface blebbing in relation to the onset of irreversible injury and cell death following anoxic and toxic injury to single hepatocytes utilizing multiparameter digitized video microscopy (MDVM) MDVM is an emerging new technology that permits single living cells to be labeled with multiple probes whose fluorescence is responsive to specific cellular parameters of interest Fluorescence images specific for each probe are collected over time, and then digitized and stored Image analysis and processing then permits quantitation of the spatial distribution of the various parameters within the single living cells Our results indicate the following: (1) formation of plasma membrane blebs accompanies all types of injury in hepatocytes; (2) cell death is a rapid event, initiated by rupture of a plasma membrane bleb, and is coincident with the onset of irreversible injury; (3) an increase of cytosolic free Ca2+ is not the stimulus for bleb formation or the final common pathway leading to cell death; (4) a decrease of mitochondrial membrane potential precedes loss of cell viability; (5) cytosolic pH falls by more than 1 pH unit during chemical hypoxia This acidosis protects against the onset of cell death

Cobalt exposure and cancer risk

Abstract: Cobalt is a technically important metal, used mainly as a binder in the hard-metal industry and as a constituent of many alloys. Cobalt compounds are used as drying agents in paints and laquers. Since ancient times, cobalt compounds have been used as coloring agents for pottery, ceramics, and glass. Soluble cobalt salts interfere adversely with cell division, bind irreversibly to nucleic acids in the cell nucleus, induce chromosome aberrations in plants, and are weakly mutagenic in some in vitro tests with cultured animal cells, bacteria, and yeast. Injections or implantation of cobalt metal, cobalt alloys, and cobalt compounds induced local and sometimes metastasizing sarcomas in rats, rabbits, and mice. Mouse is the least susceptible animal. The only published inhalation study with hamsters exposed to CoO aerosols remained non-positive. Indication of possible carcinogenic effects of cobalt alloys or compounds in human populations has arisen from medical use, in hard-metal industries, and at cobalt production. Unfortunately, confounding by nickel and arsenic is a major problem, and the size of most of the investigated populations has been rather small, so none of the investigations alone gives sufficient evidence of a carcinogenic effect in humans, but taken together there is an indication of a carcinogenic potential that should be explored further.

The Interaction of Inhaled Toxicants with Respiratory Tract Clearance Mechanisms

Abstract: Mecanismes de la clairance. Techniques de mesures. Effets des toxiques inhales sur la clairance mucociliaire et sur l'activite phagocytaire des macrophages alveolaires

Spontaneous Occurrence and Chemical Induction of Neurogenic Tumors in Rats — Influence of Host Factors and Specificity of Chemical Structure

Abstract: From the standpoint of hazard identification of neurooncogenic substances, the specificity of chemical structure for neurooncogenic activity, mode of administration, and influence of host factors such as the strain, sex, and age on the incidence, location, or type of spontaneous or chemically induced rat neurogenic tumors are reviewed and discussed. In addition, diagnostic problems on some of the neurogenic tumors in the practical differential diagnoses are briefly pointed out

Risk assessment of carcinogenic and noncarcinogenic chemicals.

Abstract: "Risk Assessment" is a general term used with increasing frequency by both scientists and regulators. Scientifically based risk assessments consider available toxicologic data when judging which agents pose a significant risk to the human population. The science of toxicology focuses on identifying potential hazards to human health using surrogate animal studies. Margins of Safety and establishment of ADIs (Acceptable Daily Intakes) are methods applied to animal test data to set "safe" levels of potential exposure. While the use of Safety Factors in development of the ADI can support a pragmatic conclusion of safety, this approach cannot provide estimates of the probability of harm or the degree of safety. Therefore, Quantitative Risk Assessment (QRA) methods using mathematical models have been advanced to extrapolate from animal exposures which are usually high to much lower human exposure levels where experimental response is absent. Such methodology has been applied primarily by U.S. regulatory agencies to experimental oncogenic responses to estimate the risks of chemical exposure. The present manuscript considers both methods for evaluation of chemical safety and focuses on the scientific merits and limitations of each.

Neuropsychological Effect of Lead in Occupationally Exposed Workers: A Critical Review

Abstract: In their discussion of field testing of health effects of environmental and industrial toxins, Gullion and Eckerman make the following observations which can be applied to the current literature survey: "The general inattention to methodological consistency makes it difficult to integrate the research to date into a clear picture of what is known and not known about the effects of toxic substances on human behavior. In view of the variation in methods of subject selection, measurement, and statistical analysis, the completion of a series of studies of a particular toxic substance does not assure that there has been a concurrent accumulation of reliable knowledge about the effects of that substance. Apparent replications or failures to replicate a significant relationship must be evaluated carefully, since different studies may have measured different things in different populations." Therefore, the issue of psychological and neuropsychological effects of low-level lead exposure in adults remains to be resolved in the studies reviewed. The methodologies were so varied and the cultures in which the studies were conducted so diverse that it is impossible to generalize across findings. For example, studies were conducted in the U.S., Denmark, Sweden, Finland, and Australia. Although, in some instances, equivalent versions of neuropsychological and psychological tests were used, this was generally not the case. Nevertheless, a few general statements can be made. Studies that have been carried out in recent years are beginning to pay attention to more methodology and therefore do a much better job of controlling for possible confounding variables. Also, their statistical methods are more sophisticated and reporting techniques are superior to the earlier investigations in this area. The issue of whether current blood lead levels or cumulative levels are preferable is still unresolved with regard to the relationship of neuropsychological impairment. In the area of psychosocial functioning, there appears to be at least some evidence to support the observation that increased irritability and fatigue may lead to the interpersonal problems noted in various studies. However, this observation may be related to other factors which have not been controlled for, such as the workers' attitudes toward their job, level of motivation, and overall level of mental health. With regard to neuropsychological functions, there is some suggestive preliminary evidence for subtle changes in the ability to process information quickly.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicology of fluorine-containing monomers.

Abstract: Fluorine-containing monomers form the basis for production of a large number of commercially important polymers. Most of the polymerization occurs as gas-phase reactions, hence the hazards associated with the monomers arises primarily from inhalation. The chemicals covered in this review include bromotrifluoroethylene (BTFE), chlorotrifluoroethylene (CTFE), hexafluoroacetone (HFA), hexafluoroisobutylene (HFIB), hexafluoropropylene (HFP), perfluorobutylene (PFBE), tetrafluoroethylene (TFE), trichloropropene (TFP), vinyl fluoride (VF), and vinylidene fluoride (VF2). The amount of toxicologic information available on the compounds is relatively small and for certain of these the information consists is short-term or acute, hence the current need to make predictions of biologic activity based on analogy or chemical reactivity is great. In animal models and in man, these monomers may be absorbed into the body at varying rates and the metabolism ranges from extensive to little in a species, dose, and chemical specific fashion. The major toxicologic target of these materials is the kidney, and the degree of involvement depends greatly on the excretion patterns and metabolic profiles of the monomers. However, other target sites exist, such as the reproductive system for HFA, making the use of structure-activity relationships difficult.

The concept of critical levels of toxic heavy metals in target tissues.

Abstract: The high reactivity of heavy metals with biological systems is well documented, although some disagreement remains on the precise dose-effect relationships involved. This represents a question of considerable importance, especially in attempts to assess the risks of exposure. The implicit assumption is usually made that a threshold concentration of specific metals exists in the most sensitive target organ, so that an increased frequency of functional lesions will be expected if this threshold is exceeded. The threshold for the metal defines its so-called critical level, and this review was written in order to examine the theoretical and practical difficulties in establishing such a level. Among these may be cited, for instance, the dependence of what constitutes the target tissue on the speciation of the metal, the changes in apparent critical level with rate and route of metal administration, the short half-life of some of the metals as well as their compartmentation in the tissues, and the consi...

Effect of cis-platinum on heme, drug, and steroid metabolism pathways: possible involvement in nephrotoxicity and infertility.

Abstract: cis-Platinum, a coordination complex of platinum, is highly effective against a number of human tumors, including steroid-dependent tumors such as testicular and prostatic cancers. It is generally assumed that DNA is the cellular target responsible for the antitumor activity of the drug. Much evidence, however, has been gathered in recent years suggesting that cis-platinum has major effects on the endocrine system, particularly the hypothalamic-pituitary-testis steroidogenesis axis, and severely disrupts the normal production of testosterone. In the axis, testis is the prime target, where the LH receptor-binding capacity of Leydig cells is decreased by nearly 80%. Within the testis, the mitochondrial cytochrome P-450scc and side-chain cleavage activity are markedly depressed and the microsomal 17 alpha-hydroxylase activity and cytochrome P-450 concentration are decreased; side-chain cleavage activity is rate-limiting in testosterone production. The effects are not limited to the testis cytochrome P-450, but extend to other organs including the liver and the kidney cytochromes. In the liver, a feminization of the cytochromes P-450 profile is produced, and hence the biotransformation of endogenous steroids as well as that of exogenous chemicals is affected. In the kidney, cis-platinum appears to be the most effective inducer of cytochrome P-450, whereby the biotransformation of the prostaglandins and fatty acids could be altered. The spectrum of the effects of cis-platinum on cytochrome P-450-dependent drug metabolism and steroid hydroxylation activity mimic those produced by hypophysectomy and are for the most part reversed by the anterior pituitary hormones. These findings suggest the possibility that general feminization of steroidogenesis caused by cis-platinum may significantly contribute to the activity of cis-platinum against hormone-dependent tumors.