Showing papers in "Critical Reviews in Toxicology in 1992"

The human hepatic cytochromes P450 involved in drug metabolism.

Abstract: The cytochromes P450 are a superfamily of hemoproteins that catalyze the metabolism of a large number of xenobiotics and endobiotics. The type and amount (i.e., the animal's phenotype) of the P450s expressed by the animal, primarily in the liver, thus determine the metabolic response of the animal to a chemical challenge. A majority of the characterized P450s involved in hepatic drug metabolism have been identified in experimental animals. However, recently at least 12 human drug-metabolizing P450s have been characterized at the molecular and/or enzyme level. The characterization of these P450s has made it possible to "phenotype" microsomal samples with respect to their relative levels of the various P450s and their metabolic capabilities. The purpose of this review is to compare and contrast the human P450s involved in drug metabolism with their related forms in the rat and other experimental species.

Aquatic insects and trace metals: bioavailability, bioaccumulation, and toxicity.

Abstract: The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physicochemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.

The pathogenesis of organophosphate polyneuropathy.

Abstract: This review discusses the facts regarding organophosphateinduced delayed polyneuropathy (OPIDP) as they are related to its pathogenesis rather than being a comprehensive review of all available data. Neuropathy target esterase (NTE) is considered to be the molecular target for OPIDP which is affected by several esterase inhibitors. Such inhibitors are ranked according to their toxicological effects as follows 1. Phosphates, phosphoroamidates, and phosphonates cause OPIDP when high amounts of NTE are inhibited. In most cases 70 to 80% inhibition is enough:, whereas in others much more is required. Phosphinates, carbamates, and sulfonyl halides cause either protection from or promotion of OPIDP when given before or after a neuropathic OP, respectively. Both effects are related to doses that inhibit NTE. Neuropathy is also caused by the combined treatment with a carbamate and a sulfonyl fluoride. 2.

Toxicological Principles of Metal Carcinogenesis with Special Emphasis on Cadmium

Abstract: Metals are an important and emerging class of carcinogens. At least three metals, specifically nickel, chromium, and arsenic, are confirmed human carcinogens, and several more are suspected to have carcinogenic potential in man. Considering that the list of known human carcinogens of any type is very small, it becomes clear that metals make up a substantial portion of the list. Furthermore, many metals are very potent carcinogens in laboratory animals. Despite this, relatively little attention has been given to the topic of metal carcinogenesis. The reasons for this relative lack of attention are not clear but perhaps are fostered by a perception that, because metals are the simplest of molecules, their mechanism of action must also be simple. This could not be farther from the truth and, although no clear mechanisms have emerged in the area of metal carcinogenesis, it has become apparent that they are anything but simple. Metal carcinogens possess several unique characteristics including a remark...

The multixenobiotic resistance mechanism in aquatic organisms.

Abstract: Many aquatic organisms thrive and reproduce in polluted waters. This fact indicates that they are well equipped with a defense system(s) against several toxic xenobiotics simultaneously because water pollution is typically caused by a mixture of a number of pollutants. We have found that the biochemical mechanism underlying such "multixenobiotic" resistance in freshwater and marine mussel, in several marine sponges, and in freshwater fish is similar to the mechanism of multidrug resistance (MDR) found in tumor cells that became refractory to treatment with a variety of chemotherapeutic agents. All these organisms possess a verapamil-sensitive potential to bind 2-acetylaminofluorene and vincristine onto membrane vesicles. They all express mRNA for mdr1 gene, and mdr1 protein product, the glycoprotein P170. Finally, in in vivo experiments, the accumulation of xenobiotics is enhanced in all investigated organisms in the presence of verapamil, the inhibitor of the P170 extrusion pump. The knowledge that the presence of one xenobiotic may block the pumping out, and hence accelerating accumulation, of others, may help us to understand and interpret our present and past data on different environmental parameters obtained using indicator organisms.

The Role of Iron in Oxygen-Mediated Toxicities

Abstract: The transition metal iron is capable of catalyzing redox reactions between biomolecules and oxygen that would not occur if catalytically active iron were not present. Although these biological oxidations (which are known collectively as "oxidative stress") have been implicated in numerous toxicities, the exact role of the iron catalyst remains to be elucidated. This review focuses on our current understanding of the role of iron in oxidative stress, discussing biologically relevant sources, biochemical forms, and reaction mechanisms of iron as a catalyst of biomolecular oxidations. Specific toxicities in which alterations in normal iron metabolism is thought to overwhelm the body's antioxidant defense system are presented, and future treatment regimens involving novel antioxidant drugs are discussed.

Small intestinal cytochromes P450

Abstract: Small intestinal cytochromes P450 (P450) provide the principal, initial source of biotransformation of ingested xenobiotics. The consequences of such biotransformation are detoxification by facilitating excretion, or toxification by bioactivation. P450s occur at highest concentrations in the duodenum, near the pylorus, and at decreasing concentrations distally--being lowest in the ileum. Highest concentrations occur from midvillus to villous tip, with little or none occurring in the crypts of Lieberkuehn. Microsomal P4503A, 2C8-10, and 2D6 forms have been identified in human small intestine, and P450s 2B1, possibly 2B2, 2A1, and 3A1/2 were located in endoplasmic reticulum of rodent small intestine, while P4502B4 has been purified to electrophoretic homogeneity from rabbit intestine. Some evidence indicates a differential distribution of P450 forms along the length of the small intestine and even along the villus. Rat intestinal P450s are inducible by xenobiotics--with phenobarbital (PB) inducing P4502B1, 3-methylcholanthrene (3-MC) inducing P4501A1, and dexamethasone inducing two forms of P4503A. Induction is most effectively achieved by oral administration of the agents, and is rapid--aryl hydrocarbon hydroxylase (AHH) was increased within 1 h of administration of, for example, 3-MC. AHH, 7-ethoxycoumarin O-deethylase (ECOD), and 7-ethoxyresorufin O-deethylase (EROD) have been used most frequently as substrates to characterize intestinal P450s. Dietary factors affect intestinal P450s markedly--iron restriction rapidly decreased intestinal P450 to beneath detectable values; selenium deficiency acted similarly but was less effective; Brussels sprouts increased intestinal AHH activity 9.8-fold, ECOD activity 3.2-fold, and P450 1.9-fold; fried meat and dietary fat significantly increased intestinal EROD activity; a vitamin A-deficient diet increased, and a vitamin A-rich diet decreased intestinal P450 activities; and excess cholesterol in the diet increased intestinal P450 activity. The role of intestinal P450 in toxifying or detoxifying specific xenobiotics has been clearly demonstrated to only a limited extent. However, elevated intestinal P450 levels have been indirectly linked to gastrointestinal cancer. Intestinal metabolism of 2,2,2-trifluoroethanol produces intestinal lesions with consequent systemic bacterial infection.

Mechanisms and pathology of monocrotaline pulmonary toxicity.

Abstract: Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatotoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydrogenation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.

A critical review of the toxicology of glutaraldehyde.

Abstract: Glutaraldehyde, a low molecular weight aldehyde, has been investigated for toxicity in humans and animals. Examination of this dialdehyde was indicated from previous studies with other aldehydes in which carcinogenicity of formaldehyde and toxicity of acetaldehyde and malonaldehyde have been disclosed. Information gaps concerning the actions of glutaraldehyde have been identified in this review and recommendations are suggested for additional short- and long-term studies. In particular, information regarding irritation of the respiratory tract, potential neurotoxicity, and developmental effects would assist in a complete hazard evaluation of glutaraldehyde. Further study related to disposition, metabolism, and reactions of glutaraldehyde may elucidate the mechanism of action.

Mercapturic acids, protein adducts, and DNA adducts as biomarkers of electrophilic chemicals

Abstract: The possibilities and limitations of using mercapturic acids and protein and DNA adducts for the assessment of internal and effective doses of electrophilic chemicals are reviewed. Electrophilic chemicals may be considered as potential mutagens and/or carcinogens. Mercapturic acids and protein and DNA adducts are considered as selective biomarkers because they reflect the chemical structure of the parent compounds or the reactive electrophilic metabolites formed during biotransformation. In general, mercapturic acids are used for the assessment of recent exposure, whereas protein and DNA adducts are used for the assessment of semichronic or chronic exposure. 2-Hydroxyethyl mercapturic acid has been shown to be the urinary excretion product of five different reactive electrophilic intermediates. Classification of these electrophiles according to their acid-base properties might provide a tool to predict their preference to conjugate with either glutathione and proteins or with DNA. Constant relationships appear to exist in the cases of 1,2-dibromoethane and ethylene oxide between urinary mercapturic acid excretion and DNA and protein adduct concentrations. This suggests that mercapturic acids in some cases may also play a role as a biomarker of effective dose. It is concluded that simultaneous determination of mercapturic acids, protein and DNA adducts, and other metabolites can greatly increase our knowledge of the specific roles these biomarkers play in internal and effective dose assessment. If the relationship between exposure and effect is known, similar to protein and DNA adducts, mercapturic acids might also be helpful in (individual) health risk assessment.

Toxicology of Quinone-Thioethers

Abstract: Cytotoxicity associated with exposure to quinones has generally been attributed to either redox cycling, and the subsequent development of "oxidative stress," and/or to their interaction with cellular nucleophiles, such as protein and non-protein sulfhydryls. Glutathione (GSH) is the major non-protein sulfhydryl present in cells, and conjugation of potentially toxic electrophiles with GSH is usually associated with detoxication and excretion. However, this review discusses the biological (re)activity of quinone-thioethers. For example, quinone-thioethers are (1) capable of redox cycling (2) substrates for, and inhibitors of, a variety of enzymes (3) methemoglobinemic (4) potent nephrotoxicants (5) DNA reactive and (6) may contribute to quinone-mediated carcinogenicity and neurotoxicity. The ubiquitous nature of quinones, and the high intracellular concentrations of GSH, ensures that cells and tissues will be exposed to quinone-thioethers. The toxicological importance of quinone-thioethers in quinone-mediated toxicities therefore deserves further attention.

Evaluation of the sensory irritation test for the assessment of occupational health risk

Abstract: Many occupational exposure limits (OELs) are based on irritation. A sensory irritation test has been developed based on trigeminal nerve stimulation in the nasal mucosa of rodents which results in a decreased respiratory frequency. The RD50, the concentration inducing a 50% decrease in the respiratory rate, was proposed for the assessment of OELs. The reproducibility within one laboratory appeared to be satisfactory, but interlaboratory differences may be larger. Intra- and interspecies differences were inconsistent. Other effects (pulmonary irritation, toxicity) may interfere with trigeminal nerve stimulation. The effects of mixed and repeated exposures (the occurrence of "sensitization" and "(cross-)tolerance") are evaluated. Severe toxicity was observed in animals exposed below the RD50 for some compounds. A quantitative evaluation with respect to human data was not possible. The suitability of the test for the assessment of an OEL is doubted. The best purpose will be as an upper range-finding study for subacute or chronic toxicity experiments.

Environmental concentrations and aquatic toxicity data on diflubenzuron (dimilin).

Abstract: The insecticide diflubenzuron (DFB) is commonly used in various mid-Atlantic states for suppression of gypsy moths in hardwood forests. DFB is potentially toxic to nontarget biota because it can enter aquatic systems through aerial application or runoff after precipitation events. Based on this concern, the objectives of this study were to: (1) compile, review, and synthesize literature on the fate, persistence, and environmental concentrations of DFB in both freshwater and saltwater environments; (2) compile, review, and synthesize acute and chronic aquatic toxicity data on DFB effects on freshwater and saltwater organisms; (3) assess possible risk to aquatic biota associated with the use of this insecticide in one specific area (Maryland); and (4) recommend future research based on the data gaps identified from this study. DFB has low solubility in water and exists as a technical grade (TG) and wettable powder (WP) formulation. The toxicity of both formulations is similar at concentrations less than 10 micrograms/l. Organic matter is a major factor influencing the adsorption and degradation of DFB in freshwater, saltwater, and sediment. The half-life of this insecticide in freshwater is approximately 3 days at a pH of 10 and temperature of 36 degrees C. At lower pH conditions of 6 and at the same temperature, DFB is more persistent since half-life values of approximately 9 days have been reported. The half-life of DFB in soil is less than 14 days when the particle size was approximately 2 microns. The half-life is generally greater in cool, dry soil than in hot, wet soil. Aquatic vegetation acts as a sink for DFB by gradually adsorbing the chemical and releasing it over a period of time. Freshwater organisms demonstrated a wide range of sensitivity to DFB. Sensitivity was dependent on body composition (i.e., exo- vs. endoskeleton), trophic level, and life stage. During acute exposures, aquatic invertebrates were more than 25,000 times as sensitive to DFB than fishes. The most acutely sensitive species tested was the Amphipod, Hyallela azteca (96-h LC50 = 1.84 micrograms/l). A mature Plecopteran, Skwala sp., was the most resistant invertebrate species tested in acute tests (96-h LC50 greater than 100,000 micrograms/l). In chronic tests, DFB concentrations of 1 microgram/l or greater were reported to eliminate populations of various Plecopteran (stoneflies) and Ephemeropteran (mayflies) species after 1 month of exposure. A 30-day LC50 of 0.1 micrograms/l DFB was also reported for the Tricopteran, Clistorinia magnifica.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiotoxicity of vasodilators and positive inotropic/vasodilating drugs in dogs: an overview.

Abstract: Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic/ vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterns occurring in dogs. A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adeq...

Assessment of the Carcinogenicity of the Nonnutritive Sweetener Cyclamate

Abstract: The weight of the evidence from metabolic studies, short-term tests, animal bioassays, and epidemiological studies indicates that cyclamate (CHS) is not carcinogenic by itself; however, there is evidence from in vitro and in vivo studies in animals that implies it may have cancer-promoting or cocarcinogenic activity. Epidemiological studies indicate that the use of nonnutritive sweeteners (CHS and saccharin) has not resulted in a measurable overall increase in the risk of bladder cancer in individuals who have ever used these products. No epidemiological information exists on the possible associations of these sweeteners and cancers other than those of the urinary tract. It is recommended that (1) no further studies on the metabolism of CHS to evaluate its carcinogenicity are required since no potentially hazardous metabolites have been appreciably detected in humans; (2) no further animal bioassays to test for the carcinogenicity of CHS by itself are necessary; (3) the studies in rodents that suggest a promotional or cocarcinogenic effect of CHS should be repeated because they cannot be ruled out; (4) because the significance to human health of a positive outcome of such studies is uncertain, additional research aimed at understanding the predictive value for human health of such results and more generic studies to develop well-validated systems that can be relied on in the assessment of cancer-promoting agents are recommended; (5) in populations where CHS continues to be used, epidemiological monitoring should be continued to determine whether there is an increased risk of cancer in humans who are heavy or long-term users or for those observed long after first exposure. In such monitoring, other cancer sites--in addition to the bladder--should be considered.

Human exposure to 2,3,7,8-TCDD and risk of cancer.

Abstract: Most of the evidence for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans has centered around whether it causes malignant lymphomas (ML) and soft-tissue sarcomas (STS). A critical review of the literature indicates that the evidence does not support a causal role for TCDD in the etiology of ML. For STS, the evidence does not specifically incriminate TCDD either, although there is room for doubt. Cancers of other sites, particularly of the respiratory system and thyroid which were found to be statistically significantly in excess in either of the two largest studies of combined cohorts of occupationally exposed workers, were identified as candidate tumors for which a possible etiological role of TCDD might need investigation in future studies.

Determination of mercapturic acid excretions in exposure control to toxicants.

Abstract: Toxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.