Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: a QSAR comparative analysis∗.

Alternative methods, including quantitative structure-activity relationships (QSAR), are being used increasingly when appropriate data for toxicity evaluation of chemicals are not available. Approximately 40 mono-hydroxylated polychlorinated biphenyls (OH-PCBs) have been identified in humans. They represent a health and environmental concern because some of them have been shown to have agonist or antagonist interactions with human hormone receptors. This could lead to modulation of steroid hormone receptor pathways and endocrine system disruption. We performed QSAR analyses using available estrogenic activity (human estrogen receptor ER alpha) data for 71 OH-PCBs. The modelling was performed using multiple molecular descriptors including electronic, molecular, constitutional, topological, and geometrical endpoints. Multiple linear regressions and recursive partitioning were used to best fit descriptors. The results show that the position of the hydroxyl substitution, polarizability, and meta adjacent un-substituted carbon pairs at the phenolic ring contribute towards greater estrogenic activity for these chemicals. These comparative QSAR models may be used for predictive toxicity, and identification of health consequences of PCB metabolites that lack empirical data. Such information will help prioritize such molecules for additional testing, guide future basic laboratory research studies, and help the health/risk assessment community understand the complex nature of chemical mixtures.

Acrolein health effects.

Acrolein is a chemical used as an intermediate reactive aldehyde in chemical industry. It is used for synthesis of many organic substances, methionine production, and methyl chloride refrigerant. The general population is exposed to acrolein via smoking, second-hand smoke, exposure to wood and plastic smoke. Firefighters and population living or working in areas with heavy automotive traffic may expose to higher level of acrolein via inhalation of smoke or automotive exhaust. Degradation of acrolein in all environmental media occurs rapidly, therefore, environmental accumulation is not expected. Acrolein degrade in 6A days when applied to surface water, and it has not been found as a contaminant in municipal drinking water. Acrolein vapor may cause eye, nasal and respiratory tract irritations in low level exposure. A decrease in breathing rate was reported by volunteers acutely exposed to 0.3A ppm of acrolein. At similar level, mild nasal epithelial dysplasia, necrosis, and focal basal cell metaplasia have been observed in rats. The acrolein effects on gastrointestinal mucosa in the animals include epithelial hyperplasia, ulceration, and hemorrhage. The severity of the effects is dose dependent. Acrolein induces the respiratory, ocular, and gastrointestinal irritations by inducing the release of peptides in nerve terminals innervating these systems. Levels of acrolein between 22 and 249 ppm for 10 min induced a dose-related decrease in substance P (a short-chain polypeptide that functions as a neurotransmitter or neuromodulator).

ATSDR evaluation of health effects of benzene and relevance to public health.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of portions of the Toxicological Profile for Benzene. The primary purpose of this article is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of benzene. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

ATSDR evaluation of potential for human exposure to benzene.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of portions of the toxicological profile for benzene. The primary purpose of this article is to provide interested individuals with environmental information on benzene that includes production data, environmental fate, potential for human exposure, analytical methods, and a listing of regulations and advisories.

Acrolein environmental levels and potential for human exposure.

This article provides environmental information on acrolein including environmental fate, potential for human exposure, analytical methods, and a listing of regulations and advisories. Acrolein may be released to the environment in emissions and effluents from its manufacturing and use facilities, in emissions from combustion processes (including cigarette smoking and combustion of petrochemical fuels), from direct application to water and waste water as a slimicide and aquatic herbicide, as a photooxidation product of various hydrocarbon pollutants found in air (including propylene and 1,3-butadiene), and from land disposal of some organic waste materials. Acrolein is a reactive compound and is unstable in the environment. The general population may be exposed to acrolein through inhalation of contaminated air and through ingestion of certain foods. Important sources of acrolein exposure are via inhalation of tobacco smoke and environmental tobacco smoke and via the overheating of fats contained in all living matter. There is potential for exposure to acrolein in many occupational settings as the result of its varied uses and its formation during the combustion and pyrolysis of materials such as wood, petrochemical fuels, and plastics.

Prediction of the health effects of polychlorinated biphenyls (PCBs) and their metabolites using quantitative structure-activity relationship (QSAR).

Polychlorinated biphenyls (PCBs) are a group of 209 persistent environmental contaminants that are slightly different but structurally related. PCBs are known to induce a variety of health effects and often have been toxicologically tested as complex commercial mixtures (Aroclors) but environmental exposure occurs separately to a small number of specific congeners. Recently, the Third National Report on Human Exposures to Environmental Chemicals, an assessment of exposure data of the National Health and Nutrition Examination Survey (NHANES), identified 35 individual PCB congeners in the U.S. population. These types of findings necessitate the toxicity evaluation of individual congeners but adequate toxicity data for most individual PCB congeners are not available. Due to this, a quantitative structure-activity relationship (QSAR) approach was used to assess the potential mutagenesis and carcinogenesis of individual congeners and their possible metabolites. The predictions were analyzed to define the underlying generalizations between the parent PCBs, their metabolites, and some important toxicological endpoints. This analysis reveals that (1) mono and di-chlorinated PCBs and their metabolites can be potential mutagens; (2) PCB benzoquinone metabolites could be carcinogenic but the weight of evidence is poor. These results support the hypothesis that environmental exposure to some PCBs and/or their metabolites could produce mutagenicity and/or carcinogenicity. Hence, these data should be considered as priority toxicological testing data needs. As with all computational toxicology analytical findings, these conclusions must yield to empirical data as they become available.

Comparative impact of live chicken infectious anaemia virus vaccine versus natural exposure in meat chicken breeders on immunity to infectivity by CIA and inclusion body hepatitis viruses in their offspring.

The immunology and histopathology and the distribution of viral antigen in infections with chicken infectious anaemia virus (CIAV) and inclusion body hepatitis virus (IBHV) were compared in the broiler offspring of CIAV-vaccinated meat chicken breeders versus those in the offspring of breeders naturally exposed to field CIAV. No significant difference in the humoral antibody level specific for CIAV was observed between 5 and 33 weeks of age in the two breeder groups (p > 0.05). The maternal humoral immunity to CIAV in the day-old offspring of the groups did not differ significantly (p > 0.05). The humoral immunity to CIAV at 40 days of age indicated an absence of clinical signs of CIAV in the broiler offspring of both groups of breeders and this was associated with mean serum thymulin levels in offspring of both groups not differing significantly at 1 or 40 days of age. Histopathological and immunofluorescence observations did not differ significantly in the offspring of either group by CIAV or IBHV.

Evaluation of 12 stabilizers in a developed attenuated Salmonella Enteritidis vaccine.

The development of a stable live attenuated Salmonella Enteritidis (SE) vaccine, resisting heat stress during transportation and storage in unequipped tropical and subtropical zones of the world, is highly recommended. Twelve stabilizers were individually supplemented into a 9 ml volume of sterile distilled water resulting in concentrations of 1, 2, 3, 4 and 5%. A volume of 1 ml of attenuated live SE vaccine is added over the 9 ml of each concentration of the stabilizers. The differently stabilized SE vaccines were stressed at 55 degrees C for 48 h. The lowest percent reductions in SE cell viability by specified level of each stabilizer in ascending order were: 22.3% by 2% skim milk, 55.1% by 5% bovine serum albumin (BSA), 59.2% by 4% sorbitol, 74.4% by 3% maltose, 75% by 2% honey, 91.3% by 3% histidine, 96.9% by 1% heparin, 97.5% by 4% dextrose, 97.9% by 5% lactose, 99.4% by 5% sucrose, 99.5% by 2% gelatin, and 100% by 1-5% glycerol. In narrowing the concentration levels of skim milk to include 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, and 3.00%, the 2.50% was the optimum level resulting in minimal percent reduction in SE cell viability of 18.9% after exposure to the defined heat stress.

Immunopotentiation of a developed Salmonella enterica serotype enteritidis vaccine by thymulin and zinc in meat chicken breeders.

The humoral immunity, spleen and thymus weight indices, lymphocyte count in the thymus cortex, and granuloma diameter at vaccination sites were assessed in four differently immunopotentiated groups of meat chicken breeders. Breeders in the first two groups were given a killed Salmonella enterica serotype Enteritidis (SE) vaccine subcutaneously at 15 and 19 weeks of age. Breeders in the third and fourth groups were left unvaccinated. Breeders in the first group were further immunopotentiated with zinc and thymulin. Each bird in the first group was given the immunopotentiators intraperitoneally in a volume of 0.1 ml at intervals of 3 days for a period of 3 weeks, starting at 15 weeks of age. At each time, each bird in the first group received thymulin (10 ng) and ZnCl2 (1 micromol/L), using a carboxymethyl cellulose carrier, totalling 90 ng thymulin and 9 micromol of ZnCl2 per bird. Each bird in the first three groups was challenged orally with 6.7 x 10(6) cfu/ml of highly virulent SE organisms, at an age of 22 weeks. The first group, which had received zinc and thymulin, had the earliest and highest humoral immune response to SE (p<0.05). This was observed at 2 and 4 weeks after the first vaccination. In addition, the first group had the highest mean thymus weight index, and the highest mean lymphocyte count in the thymus cortex. No significant difference was observed between the first two vaccinated groups in the mean granuloma diameter developed at the two vaccination sites 48 h after administration of the vaccine (p>0.05).

Carcinogenic effects of polychlorinated biphenyls.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of an important section of the Toxicological profile for polychlorinated biphenyls [ATSDR. 2000: Toxicological profile for polychlorinated biphenyls. Atlanta, GA: US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry.] into the scientific literature. This article focuses on the carcinogenic effects of this group of synthetic organic chemicals (polychlorinated biphenyls) in humans and animals. Information on other health effects, toxicokinetics, mechanisms of toxicity, biomarkers, interactions, chemical and physical properties, potential for human exposure, and regulations and advisories is detailed in the profile.

Effects of polychlorinated biphenyls on development and reproduction.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article, which constitutes the release of an important section of the Toxicological Profile for Polychlorinated Biphenyls (ATSDR 2000) into the scientific literature, focuses on the developmental and reproductive effects of this group of synthetic organic chemicals (PCBs) in humans and animals. Information on other health effects, toxicokinetics, mechanisms of toxicity, biomarkers, interactions, chemical and physical properties, potential for human exposure, and regulations and advisories is detailed in the profile. Interested readers are encouraged to consult the original toxicological profile for more information. Profiles can be requested from ATSDR's Information Center by telephone (1-888-42-ATSDR [1-888-422-8737] or E-mail: (atsdric@cdc.gov).

Induction of early immunopotentiation to Fimbriae of Salmonella Enteritidis (SE) by administering thymulin and zinc to SE-vaccinated chicken breeders: relationship to protection.

The purpose of this study is to attempt the induction of early immunopotentiation of antibodies specific to fimbriae of Salmonella enterica serovar Enteritidis (SE), by administering thymulin and zinc to SE-vaccinated chicken breeders, and the improvement of protection against a controlled-live challenge by SE. The first two groups of breeders were administered subcutaneously at 15 and 19 weeks of age a killed SE vaccine. Breeders of the third and fourth groups were left unvaccinated. Breeders of the first group, immunopotentiated by thymulin and zinc, were able to induce the earliest antibodies in their pooled sera at 2 weeks post the first SE-vaccination, specific to fimbriae (approximately 21 KDa) of SE. However, the second group that was only vaccinated with the same SE-vaccine produced specific antibodies to fimbriae at 3 weeks following the second vaccination (22 weeks of age). Breeders of the third group, that were neither SE-vaccinated nor immunopotentiated by thymulin and zinc, but were challenged by live SE at 22 weeks of age, were able to show specific antibodies to fimbriae at 3 weeks post challenge (25 weeks of age). The fourth group that was deprived of SE-vaccination, immunopotentiators, and challenge didn't show any background antibodies specific to SE-fimbriae. The presence of the earliest antibody-immunopotentiation to fimbriae of SE in breeders of the first group, administered thymulin and zinc, was associated with the lowest frequency of SE-infected ceca (10%) among the challenged groups. In addition, breeders of the first group were the only challenged birds resulting in absence of SE infection in their cecal tonsils. The first group-vaccinated, immunopotentiated, and challenged, and the second group-vaccinated and challenged only resulted in breeders with absence of SE infection in their oviducts and spleens. In conclusion, immunopotentiation of chicken breeders by thymulin and zinc induces the earliest specific antibodies to fimbriae of SE associated with the lowest frequency of SE-infected ceca, and absence of SE infection from cecal tonsils, oviducts and spleens.

Effects of polychlorinated biphenyls on the nervous system.

The neurological effects of polychlorinated biphenyls (PCBs) have been extensively investigated in humans and in animals. The main focus in human studies has been on the effects in neonates and young children, although studies of adults have also been conducted. A great deal of concern exists that even low levels of PCBs transferred to the fetus across the placenta may induce long-lasting neurological damage. Because PCBs are lipophilic substances, there is also concem that significant amounts might be transferred to nursing infants via breast milk. Studies in humans who consumed large amounts of Great Lakes fish contaminated with environmentally persistent chemicals, including PCBs. have provided evidence that PCBs are important contributors to subtle neurobehavioral alterations observed in newborn children and that some of these alterations persist during childhood. Some consistent observations at birth have been motor immaturity and hyporeflexia and lower psychomotor scores between 6 months and 2 years old. There is preliminary evidence that highly chlorinated PCB congeners, which accumulate in certain fish, are associated with neurobehavioral alterations seen in some newbom children. Subtle neurobehavioral alterations have also been observed in children bom to mothers in the general population with the highest PCB body burdens. Because of the limitations of epidemiological studies, these effects cannot be attributed entirely to PCB exposure. In one general population study, there was strong evidence that dioxins, as well as PCBs, were contributors to the neurobehavioral effects seen in exposed children. Children born to women who accidentally consumed rice oil contaminated with relatively high amounts of PCBs and chlorinated dibenzofurans (CDFs) during pregnancy also had neurodevelopmental changes. Studies in animals support the human data. Neurobehavioral alterations have been also observed in rats and monkeys following prenatal and/or postnatal exposure to commercial Aroclor mixtures, defined experimental congener mixtures, single PCB congeners, and Great Lakes contaminated fish. In addition, monkeys exposed postnatally to PCB mixtures of congeneric composition and concentration similar to that found in human breast milk showed learning deficits long after exposure had ceased. A few other generalizations can be made from the data in animals. It appears that ortho-substituted PCB congeners are more active than coplanar PCBs in modifying cognitive processes. In addition, one effect observed in both rats and monkeys--deficits on delayed spatial alternation--has been known to be induced by exposure to ortho-substituted PCBs, defined experimental mixtures, and commercial Aroclors. Both dioxin-like and non-dioxin-like PCB congeners have been shown to induce neurobehavioral alterations in animals. Changes in levels of neurotransmitters in various brain areas have also been observed in monkeys, rats, and mice. Of all the observed changes, the most consistent has been a decrease in dopamine content in basal ganglia and prefrontal cortex, but further research is needed before specific neurobehavioral deficits can be correlated with PCB-induced changes in specific neurotransmitters in specific brain areas.

ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: health effects, toxicokinetics, human exposure, and environmental fate.

This document provides public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of mirex and chlordecone. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. Additional substances will be profiled in a series of manuscripts to follow.

A review of the carcinogenicity of chemicals most frequently found at National Priorities List sites.

Several studies have shown that numerous National Priorities List (NPL) sites have been contaminated with arsenic (747), cadmium (791), chloroform (596), or nickel (664). The National Toxicology Program (NTP, 1991) has classified these substances as known human carcinogens (arsenic and certain arsenic compounds) or as substances that may reasonably be anticipated to be carcinogens (cadmium and certain cadmium compounds, chloroform, and nickel and certain nickel compounds). The general population is probably exposed to low levels of these hazardous substances through drinking water, eating food, or inhaling contaminated air. People working or living near industries and facilities that manufacture and use chloroform, nickel, arsenic, or cadmium may be exposed to higher than background levels of these hazardous substances. Multiple pathways of exposure may exist for populations near hazardous waste sites. For example, high levels of chloroform (1,890 ppb) were found in well water near a waste site; high levels of cadmium exposure may exist for individuals living near cadmium-contaminated waste sites.

Pivotal role of hepatocellular regeneration in the ultimate hepatotoxicity of CCl4 in chlordecone-, mirex-, or phenobarbital-pretreated rats.

Our earlier histomorphometric and biochemical studies suggested that the progressive phase of the interactive toxicity of chlordecone (CD) + CCl4 involves suppression of hepatocellular regeneration. The objective of the present work was to correlate hepatocellular regeneration with CCl4 (100 microliters/kg)-induced hepatotoxicity in rats maintained for 15 days on a normal (N) diet, relative to the regenerative response in rats maintained on a diet containing either 10 ppm CD, 225 ppm phenobarbital (PB), or 10 ppm mirex (M). Hepatocellular regeneration was assessed by measuring DNA and 3H-thymidine (3H-T) incorporation, followed by autoradiographic analysis of liver sections. Hepatotoxicity was assessed by measuring plasma transaminases (aspartate and alanine) followed by histopathological observations of liver sections for necrotic, swollen, and lipid-laden cells. Lethality studies were also carried out to assess the consequence of hepatotoxicity on animal survival. Dietary 10 ppm CD potentiated the hepatotoxicity of CCl4 to a greater extent than PB or M, as evidenced by elevations in plasma enzymes. Although the serum enzymes were significantly elevated in PB rats in contrast to the slight elevations in N and M rats, they returned to normal levels by 96 hr. However, serum enzyme elevations in CD rats were progressive with time until death of the animals. Actual liver injury by CCl4 was greater in PB- than in CD-pretreated rats, as evidenced by histopathological observations. A 100% mortality occurred in CD-pretreated rats at 60 hr after CCl4 administration, whereas no mortality occurred in either N-, M-, or PB-pretreated rats, indicating recovery from liver injury. Hepatocellular nuclear DNA levels were significantly decreased starting at 6 hr after CCl4 administration to CD-pretreated rats, but not in M- or PB-pretreated rats. 3H-T incorporation into nuclear DNA as well as percentage of labeled cells showed a biphasic increase in N rats: 1 at 1-2 hr, and the other at 36-48 hr after CCl4 administration. However, only 1 peak of 3H-T incorporation at 36-48 hr was observed in the CD + CCl4 combination, which was also significantly lower when compared to that observed after the M or PB + CCl4 combination treatments. These findings suggest that there is recovery in N-, PB-, or M-pretreated rats from CCl4-induced injury by virtue of the stimulated hepatocellular regeneration and tissue repair.(ABSTRACT TRUNCATED AT 400 WORDS)

Potentiation of BrCCl3 hepatotoxicity by chlordecone: biochemical and ultrastructural study.

Previous work has established that chlordecone (CD) potentiates the hepatotoxicity of BrCCl3. This interaction occurs at nontoxic levels of CD and BrCCl3. The present research was designed to investigate the mechanism governing the pathogenesis of potentiated hepatic injury and lethality induced by a low dose of BrCCl3 after dietary pretreatment with 10 ppm of CD for 15 days. On Day 16, a single dose of BrCCl3 (30 microliters/kg) was administered ip to rats maintained either on normal diet (ND) or on a diet contaminated with 10 ppm CD. Blood and liver samples were collected at 0, 3, 6, 12, 24, 36, and 48 hr after the halomethane administration for biochemical (ATP, bilirubin, glycogen) and for ultrastructural studies. A continuous increase in serum bilirubin and decrease in hepatic ATP and glycogen were observed in CD + BrCCl3 combination, indicating progressive injury, but not in other treatment groups. In ND + BrCCl3 combination, all biochemical indices were either normal or close to normal after 36 hr, suggesting complete recovery from hepatotoxicity. The most extensive ultrastructural changes characteristic of halomethane hepatotoxicity (necrosis, ballooned cells, and dilation of rough endoplasmic reticulum) were observed after the CD + BrCCl3 combination treatment. The progressive and early depletion of hepatic ATP and glycogen, and the progressive increase in toxicity along with decreased cell division in CD + BrCCl3-treated rats, indicate the association of compromised energy status and suppression of cell division and tissue repair in CD-potentiated BrCCl3 toxicity. These findings suggest that the suppression of stimulated hepatocellular regeneration results in the loss of the essential mechanism of tissue repair leading to continuation of the toxic liver injury associated with the CD + BrCCl3 combination treatment.

Bromotrichloromethane hepatotoxicity. The role of stimulated hepatocellular regeneration in recovery: biochemical and histopathological studies in control and chlordecone pretreated male rats.

It has been shown that BrCCl3 is a more potent hepatotoxin than CCl4. Pretreatment with nontoxic dietary levels of chlordecone (CD) results in amplification of BrCCl3 hepatotoxicity. The objective of this research was to investigate and compare the histopathological alterations during a time course after a low dose of BrCCl3 alone and in combination with dietary CD. Male Sprague-Dawley rats were maintained on 10 ppm dietary CD or normal diet for 15 days. On day 16, they received a single ip dose (30 microliters/kg) of BrCCl3 in corn oil (CO) vehicle or corn oil alone. Blood and liver samples were collected at 0, 3, 6, 12, 24, 36, 48, 72, 96, and 120 hr for serum enzymes and histopathological examination, respectively. Serum enzymes (SDH, ALT, AST) were significantly (p less than 0.05) elevated in rats receiving the CD + BrCCl3 combination in comparison to BrCCl3 alone. For 48 hr, a continuous increase in serum enzyme activities was detected in rats treated with CD + BrCCl3 combination, but not in the rats receiving other treatments (ND + BrCCl3, ND + CO, or CD + CO). The most extensive hepatolobular necrosis was observed in rats treated with the CD + BrCCl3 combination. Thirty-six hr after the administration of BrCCl3 to rats maintained on normal diet, high mitotic activity was observed, which continued through 72 hr resulting in complete restoration of hepatolobular structure. In contrast, rats receiving the combination of CD + BrCCl3 exhibited minimal and belated hepatomitotic activity for a short period of time, resulting in progressive hepatic failure, culminating in animal death. In conclusion, hepatotoxicity of a low dose of BrCCl3 alone appeared to be overcome via stimulated hepatocellular regeneration and hepatolobular restoration. CD appears to amplify BrCCl3 hepatotoxicity via interference with this hormetic mechanism, permitting a progressive and continued hepatic injury leading to complete hepatic failure, culminating in animal death.