Showing papers in "Environmental Health Perspectives in 1990"

Mechanism of action of organophosphorus and carbamate insecticides.

Abstract: Organophosphorus and carbamate insecticides are toxic to insects and mammals by virtue of their ability to inactivate the enzyme acetylcholinesterase. This review addresses the mechanism of inhibition of acetylcholinesterase by organophosphorus and carbamate esters, focusing on structural requirements necessary for anticholinesterase activity. The inhibition of acetylcholinesterase by these compounds is discussed in terms of reactivity and steric effects. The role of metabolic activation or degradation in the overall intoxication process is also discussed.

Uncouplers of oxidative phosphorylation.

Abstract: Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound.

Toxicity and Carcinogenicity of Potassium Bromate-A New Renal Carcinogen

Abstract: Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

Transplacental transport of lead.

Abstract: Neurotoxicity is the major health effect from exposure to lead for infants and young children, and there is current concern regarding possible toxic effects of lead on the child while in utero. There is no placental-fetal barrier to lead transport. Maternal and fetal blood lead levels are nearly identical, so lead passes through the placenta unencumbered. Lead has been measured in the fetal brain as early as the end of the first trimester (13 weeks). There is a similar rate of increase in brain size and lead content throughout pregnancy in the fetus of mothers in the general population, so concentration of lead probably does not differ greatly during gestation unless exposure of the mother changes. Cell-specific sensitivity to the toxic effects of lead, however, may be greater the younger the fetus. Lead toxicity to the nervous system is characterized by edema or swelling of the brain due to altered permeability of capillary endothelial cells. Experimental studies suggest that immature endothelial cells forming the capillaries of the developing brain are less resistant to the effects of lead, permitting fluid and cations including lead to reach newly formed components of the brain, particularly astrocytes and neurons. Also, the ability of astrocytes and neurons to sequester lead in the form of lead protein complexes occurs only in the later stages of fetal development, permitting lead in maturing brain cells to interact with vital subcellular organelles, particularly mitochondria, which are the major cellular energy source. Intracellular lead also affects binding sites for calcium which, in turn, may affect numerous cell functions including neurotransmitter release.

Mechanisms of general anesthesia.

Abstract: Although general anesthetics are often said to be nonspecific agents, it is likely that they act at a much more restricted set of target sites than commonly believed. The traditional view has been that the primary targets are lipid portions of nerve membranes, but recent evidence shows that the effects on lipid bilayers of clinically relevant levels of anesthetics are very small. Effects on most proteins are also small, but there are notable examples of proteins that are extremely sensitive to anesthetics and mimic the pharmacological profile of anesthetic target sites in animals. Such target sites are amphiphilic in nature, having both hydrophobic and polar components. The polar components appear to behave as good hydrogen-bond acceptors but poor hydrogen-bond donors. Although the targets can accept molecules with a wide variety of shapes and chemical groupings, they are unaffected by molecules exceeding a certain size. Overall, the data can be explained by supposing that the primary target sites underlying general anesthesia are amphiphilic pockets of circumscribed dimensions on particularly sensitive proteins in the central nervous system.

Effects of fiber characteristics on lung deposition, retention, and disease

Abstract: There is abundant epidemiologic evidence that asbestos fibers can cause lung fibrosis (asbestosis), bronchial cancer, and mesothelioma in humans, as well as limited evidence for such effects in workers exposed to slag and rockwool fibers. Epidemiological evidence for human disease from inhalation exposures to conventional fibrous glass is negative. While health concerns based on the morphological and toxicological similarities between man-made fibers and asbestos are warranted, it is important to note that most of the toxicological evidence for glass fiber toxicity in laboratory animals is based on nonphysiological exposures such as intratracheal instillation or intraperitoneal injection of fiber suspensions. Man-made fibers have produced lung fibrosis and mesotheliomas in such tests, albeit at much lower yields than asbestos. For all durable mineral fibers, critical length limits must be exceeded to warrant concern about chronic toxicity; i.e., 2 microns for asbestosis, 5 microns for mesothelioma, and 10 microns for lung cancer. Fiber width must be less than 0.1 microns for mesothelioma, and larger than this limit for asbestosis and lung cancer. The human health risks for most fibrous glass products are either low or negligible for a variety of reasons. First, most commercial fibrous glass products have mean fiber diameters of approximately 7.5 microns, which results in mean aero-dynamic diameters approximately 22 microns. Thus, most glass fibers, even if dispersed into the air, do not penetrate into the lung to any great extent. Second, the small fraction of smaller diameter fibers that do penetrate into the lungs are not persistent within the lungs for most fibrous glass products due to mechanical breakage into shorter lengths and overall dissolution.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of daily mortality to suspended particulates in Santa Clara County, 1980-1986.

Abstract: This paper explores the relationship between daily mortality and suspended particulates in Santa Clara County, CA, for years 1980 to 1986. An association was found between high particulate concentr...

Cellular responses to oxidative stress: the [Ah] gene battery as a paradigm.

Abstract: A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in wh...

Lead toxicity: from overt to subclinical to subtle health effects.

Abstract: Although the toxicity of lead was recognized centuries ago, concern was restricted to overt symptoms: colic, encephalopathy, anemia, or renal disease. Two major reasons for lack of progress in restricting toxicity were that interest was limited to occupational exposures and there was lack of awareness of specific biochemical or metabolic effects. Identification of subclinical effects has been possible the last 15 or 20 years because of the development of sensitive measures to detect cognitive and behavioral changes that are not apparent clinically and because of methods to measure the reduced activity of heme enzymes. This progress was driven by basic and clinical research that resulted in a better understanding of cellular toxicology. The new awareness prompted the lowering of acceptable occupational exposures, as measured by blood lead from 80 to 40 to 60 micrograms/dL range, and the establishment of maximum recommended exposures in children to a blood lead level of 25 micrograms/dL. Lowering the lead content in gasoline has been accomplished by a nearly 50% decrease in average blood levels of persons in the United States (NHANES II data). Current research implicates lead as a contributing etiologic factor in a number of common diseases affecting large portions of the population such as subtle cognitive and neurological deficits, hypertension, congenital malformations, immunotoxicity, and deficits in growth and development. For each of these disorders there may be multiple etiologic factors; the scientific challenge is to develop sensitive methodology to detect the specific role of lead. Other potential subtle health effects include the influence of small amounts of lead on cell proliferation and lead as a cofactor in carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Rules for distinguishing toxicants that cause type I and type II narcosis syndromes.

Abstract: Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed.

Overview of herbicide mechanisms of action.

Abstract: Commercial herbicides exhibit many different mechanisms of action Several enzymes involved in biosynthesis of amino acids are sites of action for herbicides A large number of different herbicide classes inhibit photosynthesis by binding to the quinone-binding protein, D-1, to prevent photosynthetic electron transfer Several different types of herbicides apparently cause accumulation of photodynamic porphyrins by inhibiting protoporphyrinogen oxidase Bipyridyliums and heteropentalenes cause the production of superoxide radicals by energy diversion from photosystem I of photosynthesis Lipid synthesis is the site of action of a broad array of herbicides used in controlling monocot weeds Herbicides of several classes apparently act by inhibiting mitosis through direct interaction with tubulin Several other molecular sites of herbicide action are known Despite a growing body of knowledge, the exact molecular sites of action of many herbicides are unknown Some herbicides are known to have more than one site of action Virtually all knowledge of herbicide structure-activity relationships is semiempirical In addition to site of action structure-activity relationships, herbicide structure and chemical properties also strongly influence absorption, translocation, bioactivation, and environmental stability Considering how little is known about all the potential sites of herbicide action, it is unlikely that during the next decade more than a relatively small number of site-specific herbicide structure-activity relationships will be developed

Environmental lead toxicity: nutrition as a component of intervention.

Abstract: The influence of nutritional status on susceptibility to the toxicity of lead is discussed. Emphasis is given to dietary factors of substantial clinical importance. Subtle changes in susceptibility are difficult to evaluate under conditions of overwhelming lead exposure. It is clear that subtle effects of lead exposure on neurobehavioral and cognitive development are a major concern. The role of nutrition is considered to be an adjunct to reduction of environmental lead exposure, which is the primary means of reducing adverse health effects of lead. Nutrition should be evaluated as a component of strategies to address this broad societal issue.

Parental occupation and childhood cancer: review of epidemiologic studies.

Abstract: Parental occupational exposures might affect childhood cancer in the offspring through genetic changes in the ovum or sperm or through transplacental carcinogenesis. The 24 published epidemiologic studies of this association have all used case-control designs, with controls generally selected from birth certificates or from general population sampling. Occupational exposures were inferred from job titles on birth certificates or through interviews. A large number of occupation-cancer associations have been reported, many of which were not addressed or not confirmed in other studies. Several associations have been found with consistency: paternal exposures in hydrocarbon-associated occupations, the petroleum and chemical industries, and especially paint exposures have been associated with brain cancer; paint exposures have also been linked to leukemias. Maternal exposures have received much less attention, but studies have yielded strongly suggestive results linking a variety of occupational exposures to leukemia and brain cancer. The primary limitations in this literature are the inaccuracy inherent in assigning exposure based on job title alone and imprecision due to limited study size. Although no etiologic associations have been firmly established by these studies, the public health concerns and suggestive data warrant continued research.

Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides.

Abstract: The mechanisms and sites of action of organochlorine (DDT-types and chlorinated alicyclics) and synthetic pyrethroid insecticides are presented with discussion of symptoms, physiological effects, a

Electrophiles and acute toxicity to fish.

Abstract: Effect concentrations in fish LC50 tests with directly acting electrophiles are lower than those of unreactive chemicals that act by narcosis. LC50 values of more hydrophobic reactive chemicals tend to approach those of unreactive chemicals. Quantitative studies to correlate fish LC50 data to physical-chemical properties indicate that LC50 values of reactive chemicals depend on hydrophobicity as well as chemical reactivity. In this paper, several examples will be given of chemical structures that are known as direct electrophiles. This classification might be useful to identify chemicals that are more effective at lower concentrations than unreactive compounds. Chemicals that require bioactivation are not included because almost no information is available on the influence of bioactivation on acute toxic effects in aquatic organisms.

Lead exposure in young children from dust and soil in the United Kingdom.

Abstract: A survey of metals in United Kingdom dusts and soils has confirmed widespread lead contamination with a geometric mean value for lead in surface (0-5 cm) garden soils of 266 micrograms/g and in housedusts of 561 micrograms/g (excluding old mining areas). A subsequent detailed survey of 97 householders in Birmingham with 2-year-old children showed dust lead loading in the home environment to be an important predictor of blood lead concentrations in young children, when both variables fell within the normal range for the U.K. The total estimated lead uptake by the young child was 36 micrograms/day of which 1 microgram was by inhalation and 35 micrograms by ingestion.

Airflow, gas deposition, and lesion distribution in the nasal passages.

Abstract: The nasal passages of laboratory animals and man are complex, and lesions induced in the delicate nasal lining by inhaled air pollutants vary considerably in location and nature. The distribution o...

Mortality of a cohort of workers in the styrene-butadiene polymer manufacturing industry (1943-1982).

Abstract: A cohort of 12,110 male workers employed 1 or more years in eight styrene-butadiene polymer (SBR) manufacturing plants in the United States and Canada has been followed for mortality over a 40-year period, 1943 to 1982. The all-cause mortality of these workers was low [standardized mortality ratio (SMR) = 0.81] compared to that of the general population. However, some specific sites of cancers had SMRs that exceeded 1.00. These sites were then examined by major work divisions. The sites of interest included leukemia and non-Hodgkin's lymphoma in whites. The SMRs for cancers of the digestive tract were higher than expected, especially esophageal cancer in whites and stomach cancer in blacks. The SMR for arteriosclerotic heart disease in black workers was significantly higher than would be expected based on general population rates. Employees were assigned to a work area based on job longest held. The SMRs for specific diseases differed by work area. Production workers showed increased SMRs for hematologic neoplasms and maintenance workers, for digestive cancers. A significant excess SMR for arteriosclerotic heart disease occurred only in black maintenance workers, although excess mortality from this disease occurred in blacks regardless of where they worked the longest. A significant excess SMR for rheumatic heart disease was associated with work in the combined, all-other work areas. For many causes of death, there were significant deficits in the SMRs.

An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program.

Abstract: Since the establishment of the National Toxicology Program (NTP), there have been gradual changes in strategies to evaluate the overall toxicity of chemicals as well as their carcinogenic potential. The spectrum of toxicologic information sought on selected chemicals has been broadened by the multidisciplinary approach to evaluating chemicals. This paper describes the scientific rationale and experimental processes used by NTP in designing studies. Also, an outline of current NTP protocols are given for prechronic and chronic toxicity/carcinogenicity studies.

Cigarette smoking and cancer mortality risk in Japanese men and women--results from reanalysis of the six-prefecture cohort study data.

Abstract: In 1965 a cohort of 265,000 residents of 29 public health districts in six prefectures throughout Japan was established and followed between 1966 and 1981. By using survival analysis based on Poisson regression models adjusted for age, prefecture of residence, and occupation, a statistically significant dose-response relationship between cigarette smoking and mortality rate was found for cancers of the liver, pancreas, and lung in both sexes; cancers of the oral cavity, esophagus, stomach, larynx, and bladder in men; and cancer of the uterus in women. The magnitudes of relative risks were only slightly affected by adjustment for prefecture of residence or occupation. Analysis using linear relative risk models revealed that the inclusion of a quadratic term for the amount of daily cigarette consumption in addition to the linear term improved the fit of the model significantly for cancers of the esophagus and stomach in men and cancer of the stomach in women. The sex ratio of gastric cancer mortality was higher among smokers than among nonsmokers. When the follow-up period was divided into four 4-year intervals, it was noted that the relative mortality risk associated with lung cancer among males increased significantly during these time periods.

Mode of action and the assessment of chemical hazards in the presence of limited data: use of structure-activity relationships (SAR) under TSCA, Section 5.

Abstract: Section 5 of the Toxic Substances Control Act (TSCA) requires that manufacturers and importers of new chemicals must submit a Premanufacture Notification (PMN) to the U.S. Environmental Protection Agency 90 days before they intend to commence manufacture or import. Certain information such as chemical identity, uses, etc., must be included in the notification. The submission of test data on the new substance, however, is not required, although any available health and environmental information must be provided. Nonetheless, over half of all PMNs submitted to the agency do not contain any test data; because PMN chemicals are new, no test data is generally available in the scientific literature. Given this situation, EPA has had to develop techniques for hazard assessment that can be used in the presence of limited test data. EPA's approach has been termed "structure-activity relationships" (SAR) and involves three major components: the first is critical evaluation and interpretation of available toxicity data on the chemical; the second component involves evaluation of test data available on analogous substances and/or potential metabolites; and the third component involves the use of mathematical expressions for biological activity known as "quantitative structure-activity relationships" (QSARs). At present, the use of QSARs is limited to estimating physical chemical properties, environmental toxicity, and bioconcentration factors. An important overarching element in EPA's approach is the experience and judgment of scientific assessors in interpreting and integrating the available data and information. Examples are provided that illustrate EPA's approach to hazard assessment for PMN chemicals.

Antecedents and correlates of improved cognitive performance in children exposed in utero to low levels of lead.

Abstract: Up to 2 years of age, children with umbilical cord blood lead levels of 10 to 25 micrograms/dL achieve significantly lower scores on tests of cognitive development than do children with lower prenatal exposures. By age 5 years, however, they appear to have recovered from, or at least compensated for, this early insult. Change in performance between 24 and 57 months of age was examined in relation to level of postnatal lead exposure and various sociodemographic factors. Among children with high prenatal lead exposure, greater recovery of function was associated with lower blood level at 57 months, higher socioeconomic status, higher Home Observation for Measurement of the Environment scores, higher maternal IQ, and female gender. The difference between the scores at 57 months of children with optimal and less optimal values on these variables generally exceed 1/2 standard deviation. Higher prenatal lead exposure is associated with an increased risk of early cognitive deficit. Furthermore, the risk that a deficit will persist through the preschool years is increased among children with high prenatal exposure and either high postnatal exposure or less optimal sociodemographic characteristics.

Lead exposure and neurobehavioral development in later infancy.

Abstract: A prospective methodology was used to assess the neurobehavioral effects of fetal and postnatal lead exposure during the first 2 years of life. Lead was measured in whole blood prenatally in mother...

The industrial production and use of 1,3-butadiene.

Abstract: This presentation provides a brief overview of the production and use of 1,3-butadiene in the United States. Starting as a coproduct of ethylene, the 1,3-butadiene monomer is extracted and purified, then transferred to consumers. Major uses of 1,3-butadiene include the manufacture of styrene-butadiene rubber, polybutadiene rubber, and adiponitrile.

Normal histology of the nasal cavity and application of special techniques.

Abstract: There are three major epithelial types in the nasal mucosa, in addition to numerous accessory structures, some of which are species specific. Without careful and consistent processing of the nose tissue, histopathologic assessment of lesions in the nasal cavity may be compromised. While formalin fixation may be used for routine review of the nasal cavity, Bouin's fixation provides better histologic detail and fewer artifacts. Decalcification is not recommended for nasal tissues to be examined by transmission electron microscopy because of the detrimental effect of decalcifying solutions on sensory cells. Three levels of the nasal cavity may be used for routine histologic review of the nasal cavity, but four or five levels may be more appropriate for certain studies.

Lead poisoning and brain cell function.

Abstract: Exposure to excessive amounts of inorganic lead during the toddler years may produce lasting adverse effects upon brain function. Maximal ingestion of lead occurs at an age when major changes are o...

Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides.

Abstract: The mechanisms and sites of action of organochlorine (DDT-types and chlorinated alicyclics) and synthetic pyrethroid insecticides are presented with discussion of symptoms, physiological effects, and selectivity. The structural requirements for toxicity are assessed, and structure-activity relationships are considered for each subclass. Lipophilicity is important for all the groups because it facilitates delivery of these neurotoxicants to the site of action in the nerve. Steric factors including molecular volume, shape, and isomeric configuration greatly influence toxicity. Electronic parameters also have been demonstrated to affect biological activity in some of the groups of insecticides, e.g., Hammett's sigma and Taft's sigma * as indicators of electronegativity. New synthetic pyrethroids continue to be developed, with varied structures and different physicochemical and biological properties.

Determinants of elevated blood lead during pregnancy in a population surrounding a lead smelter in Kosovo, Yugoslavia.

Abstract: We are prospectively examining the relation between environmental lead exposure and pregnancy outcome in cohorts of women exposed to a wide range of air lead concentrations. Titova Mitrovica, Yugoslavia, is the site of a large lead smelter, refinery, and battery factory. At midpregnancy, 602 women in T. Mitrovica and 900 women in Pristina, a non-lead-exposed control town, were interviewed. Blood was obtained for blood lead (PbB), hemoglobin, erythrocyte protoporphyrin, and serum ferritin measurements. Women were seen again at delivery, at which time maternal and umbilical cord blood samples were obtained. While many demographic and social characteristics were similar across the two towns, women in Pristina were more likely to report employment outside the home, cigarette smoking, and alcohol use during pregnancy. As expected, PbB levels were substantially higher in the smelter town. At midpregnancy, PbB geometric means were 17.1 micrograms/dL in T. Mitrovica and 5.1 micrograms/dL in Pristina; 86% of the pregnant women in T. Mitrovica, compared to 3.4% of those in Pristina, had PbB levels greater than 10 micrograms/dL. Within T. Mitrovica, distance between the home and the smelter was the most important predictor of PbB at mid-pregnancy and delivery. Husband's employment in the lead industry was associated with a significant increase in maternal PbB levels independent of place of residence. Higher maternal serum ferritin concentrations were associated with lower PbB levels, suggesting that dietary iron inhibits lead absorption. Overall, the placenta was a poor barrier to lead; the relationship between maternal PbB and umbilical cord PbB was linear across a wide range of PbB levels.

Comparative anatomy, physiology, and function of the upper respiratory tract.

Abstract: The anatomical characteristics of the upper respiratory tract of various experimental animals and man are described. There are a number of differences and similarities macroscopically and microscopically between the species. Perhaps one of the most obvious examples of anatomical differences is in the structure of the turbinates. Some of the differences could affect deposition and clearance of particles in the nasal cavities. Effects of compounds in the nasal cavity, larynx, and trachea can differ depending on the cellular composition of the mucosa.

The role of calcium ions in toxic cell injury.

Abstract: Calcium ions have been increasingly implicated as a mediator of the mechanisms generating lethal cell injury under a variety of pathologic circumstances. An overview of the various roles suggested for such alterations in cellular calcium homeostasis is presented. The central role of plasma membrane damage in the genesis of irreversible cell injury is used to divide the postulated roles for calcium ions into two major mechanisms. On the one hand, calcium ions have been proposed as mediators of the functional consequences of plasma membrane injury. An influx of extracellular calcium ions across a damaged permeability barrier and down a steep concentration gradient may convert potentially reversible injury into irreversible injury. On the other hand, alterations in intracellular calcium homeostasis are postulated to participate in the mechanisms generating potentially lethal plasma membrane injury. The release of calcium stores sequestered within intracellular organelles raises the cytosolic concentration of free calcium, a process that may activate, in turn, a number of membrane-disruptive processes. The data supporting these two distinct actions of calcium are reviewed and discussed.