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PubMed2006

Estimated cancer risk of dioxins to humans using a bioassay and physiologically based pharmacokinetic model.

The health risk of dioxins and dioxin-like compounds to humans was analyzed quantitatively using experimental data and mathematical models. To quantify the toxicity of a mixture of three dioxin congeners, we calculated the new relative potencies (REPs) for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), and 2,3,4,7,8- pentachlorodibenzofuran (PeCDF), focusing on their tumor promotion activity. We applied a liver foci formation assay to female SD rats after repeated oral administration of dioxins. The REP of dioxin for a rat was determined using dioxin concentration and the number of the foci in rat liver. A physiologically based pharmacokinetic model (PBPK model) was used for interspecies extrapolation targeting on dioxin concentration in liver. Toxic dose for human was determined by back-estimation with a human PBPK model, assuming that the same concentration in the target tissue may cause the same level of effect in rats and humans, and the REP for human was determined by the toxic dose obtained. The calculated REPs for TCDD, PeCDD, and PeCDF were 1.0, 0.34, and 0.05 for rats, respectively, and the REPs for humans were almost the same as those for rats. These values were different from the toxic equivalency factors (TEFs) presented previously (Van den Berg, M., Birnbaum, L., Bosveld, A.T.C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., Rolaf van Leeuwen, F.X., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger. L., Safe, S., Schrenk, D., Tillitt, D, Tysklind, M., Younes, M., Waern, F., Zacharewski, T., 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106, 775-792). The relative risk of excess liver cancer for Japanese people in general was 1.7-6.5 x 10(-7) by TCDD only, and 2.9-11 x 10(-7) by the three dioxins at the present level of contamination.

Animals↗
PubMed2006

[The multifaceted effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in organisms, especially dentition changes].

Dioxins are by products of various technological processes in many branches of industry and products of the combustion of chlorine compounds at low temperatures. They include polychlorated dibenzo-p-dioxins and dibenzofurans. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most dangerous to the human organism and is a model substance to define the toxicity of particular dioxins in mixture. TCDD in small doses exerts a toxic influence on embryos and maturing persons. Dioxin exposure to animals and people causes changes in the immunological system, fetus failure, and defects in fertility and in internal organs and is carcinogenic. Knowledge in this area is rather well documented and has expanded. However, there is little information about dioxin's influence on dentition development. In this review, recent literature reports and the results of own investigations of the general biological effects of dioxins, especially for dentition, are presented.

Adult↗
PubMed1995

Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea.

UNLABELLED: Veno-occlusive disease was diagnosed in an 18-month-old boy who had regularly consumed a herbal tea mixture since the 3rd month of life. The boy developed portal hypertension with severe ascites. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The tea contained peppermint and what the mother thought was coltsfoot (Tussilago farfara). The parents believed the tea aided the healthy development of their child. Pharmacological analysis of the tea compounds revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components by thin-layer chromatography, mass spectrometry and NMR spectroscopy. We calculated that the child had consumed at least 60 micrograms/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months. CONCLUSION: In all cases of veno-occlusive disease pyrrolizidine alkaloids ingestion should be excluded. The identity of collected plant material should be verified by pharmaceutically trained experts and information of composition, dosage and mode of administration should be included in guidelines for herbal preparations.

Hepatic Veno-Occlusive Disease↗
PubMed2003

Neurobehavioral evaluations of mixtures of trichloroethylene, heptachlor, and di(2-ethylhexyl)phthalate in a full-factorial design.

One approach to the toxicological evaluation of chemical mixtures is to construct full dose-response curves for each compound in the presence of a range of doses of each of the other compounds, i.e., a factorial design. This study was undertaken as part of an interdisciplinary project to evaluate a mixture of three environmental pollutants. A full-factorial design was undertaken to determine the neurobehavioral consequences of short-term repeated exposure to five dose levels each of three chemicals, in order to characterize potential two- and three-way interactions. Adult female F344 rats received (p.o.) for 10 days either one of five doses of trichloroethylene, di(2-ethylhexyl)phthalate, or heptachlor, or else one of all possible chemical combinations. Neurobehavioral evaluations were conducted using motor activity and an abbreviated functional observational battery. Response-surface analysis was applied to each of the endpoints. Hypotheses were tested based on the estimated model parameters; of primary interest was the overall test for interaction among the three chemicals. In addition, an abbreviated design was created by fitting only a subset of the data to the model. In general, significant overall interactions that deviated from response additivity were detected for most endpoints (11 of 14). All of the interactions on the neurobehavioral endpoints showed either antagonism, or else an interaction that could not be fully characterized. Often the results of the abbreviated dataset analysis were not the same as for the full-factorial design. This study was extremely intensive, in terms of the number of rats and time required for conduct of the study as well as the data analysis. These results underscore the need for more economical approaches to evaluate the toxic effects of mixtures of chemicals.

Animals↗
PubMed1996

Beyond TPH: health-based evaluation of petroleum hydrocarbon exposures.

The term "total petroleum hydrocarbons" (TPH) is a widely used, but loosely defined, parameter quantified by a number of different methodologies for expressing the aggregate amount of petroleum hydrocarbon compounds (PHCs) in a sample. Because of the shortcomings associated with comparing data from different methods, and the difficulty of assessing potential toxicities of complex mixtures of hydrocarbons, a new approach at more fully and explicitly defining the PHC composition of samples and predicting human noncancer health risks from those exposures has been developed. This new approach is the subject of this paper. This method can be used to perform site-specific risk assessments or to develop health-based cleanup standards for petroleum hydrocarbons. The technique divides the broad chemical classes of PHC (i.e., saturated versus unsaturated) into subgroups of compounds based on numbers of carbon atoms in the compounds within each subgroup. The mass of compounds in each subgroup is then translated into discrete estimates of health risk for specified exposure scenarios. The subgroups were identified from qualitative and quantitative changes in the nature of noncancer toxicities recorded in the literature. For saturated compounds, toxicity changes as carbon chain length increases (measured by numbers of carbon atoms). A "reference compound" was chosen for each range of compounds, usually because its toxicity was relatively well characterized. A published oral reference dose (RfD) was identified for these compounds, or in the absence of a published value, an oral dose-response value was developed from available toxicity information. For saturated PHCs (alkanes, cycloalkanes, and isoalkanes) the subgroups' reference compounds and assigned toxicity value used are C5 to C8 (n-hexane, 0.06 mg/kg/day); C9 to C18 (n-nonane, 0.6 mg/kg/day); and C19 to C32 (eicosane, 6.0 mg/kg/day). For unsaturated compounds (aromatics), one reference RfD was identified for all compounds: C9 through C32 (pyrene, 0.03 mg/kg/day). Dependent upon the analytical technique used for separation of compounds, the unsaturated alkenes may be grouped and subsequently quantified with either the saturate or unsaturate groups. The implications of possible association with either group and contributions to risk estimates are probably not significant. Alkenes make up a small fraction of most fuel products, and they bear structural similarity to the alkanes and are not particularly toxicologically active. If grouped analytically with the aromatics the alkene contribution to toxicity estimates would likely be minor and not be an underestimate of its true toxicity. The mass of PHC in each segment of a chromatogram is quantified and converted to a medium-specific concentration which is then entered into standard medium intake equations to arrive at a daily dose of PHC. This dose is then used with the toxicity value identified for the particular segment of the chromatogram to derive a hazard quotient. The quotients can then be summed across fractions to yield a total hazard index. The noncancer health risks from the aromatics benzene, toluene, and xylenes are evaluated separately using standard risk assessment techniques.

Alkanes↗
PubMed1991

The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice.

The toxicity of the PCB substitute Ugilec 141, a mixture of tetrachlorobenzyltoluenes (TCBTs), is compared with the toxicity of a commercial mixture of polychlorobiphenyls (Aroclor 1254) and with the model toxic PCB-congener 3,3',4,4',-tetrachlorobiphenyl (PCB-77) as a positive control. Alterations in liver weight, hepatic cytochrome P450 content and EROD and PROD activity, plasma thyroxin and retinol level, hepatic retinoid level and liver and thyroid pathology, have been studied in Ah-responsive and Ah-nonresponsive mice. Ugilec 141 proved to induce similar toxicological changes, qualitatively and quantitatively, to Aroclor 1254. Therefore Ugilec may pose a similar environmental and health risk as PCBs. The criteria for acceptance of new substances, like Ugilec 141, on the European market are discussed.

Journal Article↗
PubMed2006

Effects of separate and combined exposure to the pesticides methamidophos and chlorothalonil on the development of suckling rats.

It has been suggested that, in some cases, exposure to environmental contaminants affects children more profoundly than adults. It is important to evaluate adverse health outcomes in children, a population susceptible to toxic chemicals and mixtures. We examined the effects that maternal exposure to two pesticides had on maturational aspects of offspring development during the nursing period. Nursing female rats were exposed to 1-4mg/kg of intraperitoneal methamidophos, 200-800mg/kg of chlorothalonil, or both. The higher doses of methamidophos affected pup viability by day 21 of life. Both pesticides, alone or together, affected body weight gain of dams and offspring. Developmental milestones evaluated in the pups were incisor eruption, ear unfolding, eye opening and testis descent. Although no clear dose-response relationship was established between these milestones and exposure to methamidophos or chlorothalonil, incisor eruption was accelerated in many groups, and the majority of rat offspring exposed to methamidophos presented later ear unfolding and eye opening than did the control group offspring. Sexual maturation (testis descent) was significantly delayed in some groups. For dams and pups alike, simultaneous exposure to both pesticides was not found to have a greater toxic effect than that resulting from exposure to only one of the two. Taken together, these results demonstrate exposure-related influences on several developmental measures. Detection of more subtle effects may be improved through the use of the developmental temporal response protocols utilized in this study.

Animals↗
PubMed1996

In vitro percutaneous absorption of benzidine in complex mechanistically defined chemical mixtures.

Little work has been done on the topical absorption of the bladder carcinogen benzidine. Since humans are more likely to be exposed to chemical mixtures than to a single chemical, a program was developed in these laboratories to examine the cumulative effect of complex mixtures on percutaneous absorption of important toxicants such as benzidine. In this investigation, a mixture is defined as a physical combination consisting of a marker chemical and several other chemicals, each of which can have independent and/or synergistic effects on dermal penetration and absorption of the marker chemical. Ten mixtures, consisting of a marker chemical (benzidine, B), a solvent (acetone, A or DMSO, D), a surfactant (0 or 10% sodium lauryl sulfate, SL), a vasodilator (0 or 180 microg methyl nicotinate, M), and a reducing agent (0 or 2% SnCl2, s) were employed in this study. Isolated perfused porcine skin flaps (IPPSFs), which have proven to be a suitable in vitro model for assessing dermal absorption and toxicity, and flow-through diffusion cell systems were utilized. The extent of benzidine absorption in skin sections dosed with either B + A (0.94% dose) or B + D (1.01% dose) was similar to that when IPPSFs were dosed with either B + A (0.54% dose) or B + D (1.31% dose). However, flux vs time profiles were different when the two in vitro methods were compared. For mixtures containing (1) DMSO only or acetone only or (2) solvents containing SL + M, benzidine absorption was enhanced when compared with other mixtures. Compared to acetone, DMSO appears to enhance dermal penetration of benzidine in most of the mixtures. Compared to other mixtures evaluated, SnCl2 inhibited benzidine absorption irrespective of solvent present. SnCl2 also appears to inhibit benzidine penetration in DMSO mixtures containing SL only, but not in acetone mixtures. It is proposed that chemical-chemical interactions between benzidine and SnCl2 may be inhibiting benzidine absorption and chemical-biological interactions between M + SL and skin may be enhancing benzidine absorption. Across all mixtures, maximum observed benzidine absorption was almost 3% of the topical dose over 8 hr, but maximum penetration was 22% over the same time period which would suggest a potential for greater systemic exposure over longer time frames. This work underscores the need to study potentially toxic chemicals in mixture exposure scenarios since the interactions observed would confound risk assessment based on single chemical data.

Animals↗
PubMed1998

Molluscicidal and anti-AChE activity of tertiary mixtures of pesticides

We studied the toxicity and in vivo inhibition of acetylcholinesterase (AChE) by the organophosphate Nuvan (dichlorvos); Nuvan mixed with a mixed function oxidase inhibitor, piperonyl butoxide (PB); Nuvan with a pyrethroid Decis (deltamethrin); and a tertiary mixture of Nuvan, PB, and Decis in the snail Lymnaea acuminata. Nuvan was highly toxic to the snail and was a strong inhibitor of AChE activity. Both PB and Decis act synergistically with Nuvan when given together in a 1:5 and 1:46 ratio, respectively. When a tertiary mixture of Nuvan, Decis, and PB was given in a 1:46:5 ratio, the toxicity of the mixture was higher in comparision to the binary mixture of Nuvan + PB or Nuvan + Decis.

Journal Article↗
PubMed2003

Effects of temperature on the recovery of juvenile grayling (Thymallus thymallus) from exposure to Al+Fe.

One-summer-old graylings (Thymallus thymallus) were exposed for 6 days to water containing a mixture of 1 mg l(-1) Fe and 100 microg l(-1) Al at pH 5.5, with or without 15 mg l(-1) humic acid. A pH of 6.9 was used as a control. The experiment was performed at two test temperatures, 13 and 3 degrees C. After 1 week of exposure, half of the fish in the tank were taken for oxygen measurement and tissue sampling. The remaining half were maintained in metal-free water for a further week to assess their recovery at the two test temperatures. Fifty percent of the fish died under metal exposure at 13 degrees C, but none at 3 degrees C. Despite of the lack of mortalities at the lower temperature, surviving fish at both test temperatures suffered similar gill damage (adherence of lamellae), disturbances in ion regulation, increases in haematocrit value (Hct) and haemoglobin (Hb) concentration and reductions in oxygen consumption. The addition of humic acid prevented these changes. The reduced plasma chloride concentration, increased blood Hct value and Hb concentration recovered completely at 13 degrees C, whereas the lowered oxygen consumption recovered less completely, which may be attributed to the remaining minor gill damage (lamellar hypertrophy). At the lower temperature, the adherence of lamellae persisted after the recovery period, and oxygen consumption, therefore, remained at a very low level. The decreased plasma chloride concentration was also unable to recover. The accumulation of Al inside the gill tissue was greater at low temperature. We conclude that the acute toxicity of a mixture of Fe and Al to grayling and their subsequent ability to recovery is dependent on the exposure temperature.

Aluminum↗
PubMed1993

Toxicity study of the main alkaloids of Datura ferox in broilers.

Seeds of the weed Datura ferox are frequent contaminants of raw materials used for animal feed. These seeds produce various toxic effects and contain mainly the alkaloids scopolamine and hyoscyamine. In this 3-month toxicity study, a mixture of scopolamine and hyoscyamine (98:2) was incorporated at four total alkaloid levels (1.5, 15, 75 or 150 mg/kg feed) into a control diet fed to 100 broilers. Alkaloid feeding caused significant reductions in the body weight gain of birds, especially of those fed a dose of 150 mg alkaloid/kg feed. Growth-retarding effects, however, were transient, as no changes in body weight gain were noted after 52 days of alkaloid feeding. Alkaloid-treated broilers showed no significant differences from controls with respect to the cardiac rate and breathing frequency nor in relation to plasma aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities. In contrast, plasma leucine aminopeptidase activity was significantly reduced after 3 months in all alkaloid-fed birds. Autopsy and histological examination of tissues by light and electron microscopy revealed no pathological changes associated with alkaloid feeding. Broilers appeared generally healthy and behaved normally throughout. These data should be considered in the formulation of new, improved regulations defining the maximum allowable alkaloid content of D. ferox seeds contaminating raw materials destined for use as broiler feed.

Animal Feed↗
PubMed2006

Amended final report on the safety assessment of Oryza Sativa (rice) Bran Oil, Oryza Sativa (rice) Germ Oil, Rice Bran Acid,Oryza Sativa (rice) Bran Wax, Hydrogenated Rice Bran Wax, Oryza Sativa (rice)Bran Extract, Oryza Sativa (rice) Extract, Oryza Sativa (rice) Germ Powder, Oryza Sativa (rice) Starch, Oryza Sativa (rice) Bran, Hydrolyzed Rice Bran Extract, Hydrolyzed Rice Bran Protein, Hydrolyzed Rice Extract, and Hydrolyzed Rice Protein.

This report addresses the safety of cosmetic ingredients derived from rice, Oryza sativa. Oils, Fatty Acids, and Waxes: Rice Bran Oil functions in cosmetics as a conditioning agent--occlusive in 39 formulations across a wide range of product types. Rice Germ Oil is a skin-conditioning agent--occlusive in six formulations in only four product categories. Rice Bran Acid is described as a surfactant-cleansing agent, but was not in current use. Rice Bran Wax is a skin-conditioning agent--occlusive in eight formulations in five product categories. Industry did not directly report any use of Rice Bran Wax. Hydrogenated Rice Bran Wax is a binder, skin-conditioning agent--occlusive, and viscosity-increasing agent--nonaqueous in 11 formulations in six product categories. Rice Bran Oil had an oral LD50 of > 5 g/kg in white rats and Rice Wax had an oral LD50 of > 24 g/kg in male mice. A three-generation oral dosing study reported no toxic or teratologic effects in albino rats fed 10% Rice Bran Oil compared to a control group fed Peanut Oil. Undiluted Rice Bran Oil, Rice Germ Oil, and Hydrogenated Rice Bran Wax were not irritants in animal skin tests. Rice Bran Oil was not a sensitizer. Rice Bran Oil, Rice Germ Oil, Rice Wax, and Hydrogenated Rice Bran Wax were negative in ocular toxicity assays. A mixture of Rice Bran Oil and Rice Germ Oil had a ultraviolet (UV) absorption maximum at 315 nm, but was not phototoxic in a dermal exposure assay. Rice Bran Oil was negative in an Ames assay, and a component, gamma-oryzanol, was negative in bacterial and mammalian mutagenicity assays. Rice oils, fatty acids, and waxes were, at most, mildly irritating in clinical studies. Extracts: Rice Bran Extract is used in six formulations in four product categories. Rice Extract is a hair-conditioning agent, but was not in current use. Hydrolyzed Rice Extract is used in four formulations and current concentration of use data were provided for other uses. Hydrolyzed Rice Bran Extract, described as a skin-conditioning agent--miscellaneous, is used in two product categories. Use concentrations are in the 1% to 2% range. Rice Bran Extract is comprised of proteins, lipids, carbohydrates, mineral ash, and water. The content includes palmitic, stearic, oleic, and linoleic acids. Other components include antioxidants such as tocopherols. Rice Extract reduced the cytotoxicity of sodium chloride in male rats. Bran, Starch and Powder: Rice Bran (identified as rice hulls) is an abrasive and bulking agent in one formulation. Rice Starch is an absorbent and bulking agent in 51 formulations across a wide range of product categories. Rice Germ Powder is an abrasive and one manufacturer described an exfoliant use, but it was not reported to be used in 2002. Oral carcinogenicity studies done on components of Rice Bran (phytic acid and gamma-oryzanol) were negative. Rice Bran did not have an anticarcinogenic effect on 1,2-dimethylhydrazine-induced large bowel tumors. In cocarcinogenicity studies done using 1,2-dimethylhydrazine and other agents, with Rice Bran Oil and Rice Bran-derived hemicellulose and saccharide, tumor inhibition was observed; gamma-oryzanol did not inhibit the development of neoplasms. A decrease in cutaneous lesions in atopic dermatitis patients was reported following bathing with a Rice Bran preparation. Proteins: Hydrolyzed Rice Bran Protein and Hydrolyzed Rice Protein function as conditioning agents (hair or skin), but only the latter was reported to be used in a few products. An in vitro phototoxicity assay using UVA light found no photochemical toxicity. Rice bran protein hydrolysates are not acutely toxic, are not skin or ocular irritants in animals, are not skin sensitizers in guinea pig maximization tests, and are not irritating or sensitizing in clinical tests. Isolated cases of allergy to raw rice have been reported, but rice, in general, is considered non allergenic. The Cosmetic Ingredient Review (CIR) Expert Panel considered that safety test data available on certain of these ingredients could be extrapolated to the entire group. Although Rice Bran Extract does contain UV absorbing compounds at low concentrations, clinical experience suggested no phototoxicity would be associated with such materials. Rice derived ingredients generally are considered to be non allergenic. There were no safety test data available for Hydrolyzed Rice Extract and Hydrolyzed Rice Bran Extract, but their safety may be inferred from that of the extracts from which they are derived. Current levels of polychlorinated biphenyls (PCBs) and heavy metals in rice-derived ingredients used in cosmetics are not a safety concern. The Panel was concerned, however, that contaminants such as pesticides have been reported in Rice Bran Oil used for cooking. Pesticides and heavy metals should not exceed currently reported levels for rice-derived cosmetic ingredients. The CIR Expert Panel concluded that these rice-derived ingredients are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.

Animals↗
PubMed1987

Efficacies of mixtures of disinfectants and insecticides.

Efficacies of mixtures of diluted commercial formulations of selected insecticides and disinfectants were evaluated. Insecticides tested included representative pyrethroids (fenvalerate [Ectrin WDL and WD] and permethrin [Ectiban EC]), organophosphates (dichlorvos [Vapona EC], tetrachlorvinphos [Rabon WP] and dichlorvos/tetrachlorvinphos [RaVap EC], and a carbamate (carbaryl [Sevin S]). Disinfectants tested included representatives of cresylic acid (Biolene), cresylic acid/phenol (BioGuard X-185), phenol (1-Stroke Environ), quaternary ammonium (BioGuard S-3 and PFP-4), quaternary ammonium/formalin (DC & R), and formalin classes of disinfectants. Mixtures were tested for toxicity to two target insects (Musca domestica on plywood, Alphitobius diaperinus in litter) and two bacteria (Pseudomonas aeruginosa and Staphylococcus aureus). Of 56 mixtures evaluated, 24 showed reduced insecticidal toxicity and 35 showed reduced bactericidal activity compared with insecticides or disinfectants alone.

Animal Husbandry↗
PubMed1992

In vivo studies on halogen compound interactions. IV. Interaction among different halogen derivatives with and without synergistic action on liver toxicity.

The liver toxicity of several halogen compound mixtures have been tested. The compounds were selected on the basis of their metabolic pathways: carbon tetrachloride (CT) and trichlorobromomethane (TCBM) undergo a dehalogenation via P450-dependent enzyme system, 1,2-dichloroethane (DCE) and 1,2-dibromoethane (DBE) are mainly conjugated with the cytosolic glutathione (GSH) by means of the GSH-S-transferase. The mixture TCBM+DBE shows a more than additive action on lipid peroxidation and liver necrosis. TCBM, like CT, reduces the hepatic level of GSH-S-transferase, increasing the amount of DBE available for cytochrome P450-dependent metabolism, with the production of toxic metabolites. Thus, the behavior of the mixture TCBM+DBE is very similar to that of the mixture CT+DBE, previously reported. Mixtures composed of CT+TCBM and DCE+DBE do not show any synergistic effect on liver toxicity. The results allow one to conclude that the toxicity of mixtures of halogen compounds can be partly predicted on the basis of their metabolic pathways. When the metabolism is quite different, a synergistic toxicity can occur if one pathway interferes with a detoxification mechanism of the other compound. If the two metabolisms are very similar they produce, at most, an additive toxicity.

Alanine Transaminase↗
PubMed2006

Interactive effects of cadmium and all-trans-retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice.

BACKGROUND: Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13-cis-retinoic acid and all-trans-retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated. METHODS: Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects. RESULTS: When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive. CONCLUSIONS: The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold.

Animals↗
PubMed1991

A CCl4/CHCl3 interaction study in isolated hepatocytes: non-induced and phenobarbital-pretreated cells.

The purpose of this study was to evaluate an isolated hepatocyte model for predicting the in vivo hepatotoxicity of carbon tetrachloride (CCl4) and chloroform (CHCl3), alone and in combination. Response surface methodology (RSM) was used to analyze and describe the data. The interaction was evaluated for % initial K+ (cell injury) and % LDH leakage (cell death) in non-induced (untreated) and phenobarbital-pretreated suspended hepatocytes. CCl4 and CHCl3 were delivered alone and in combination in dimethyl sulfoxide (DMSO) to suspended hepatocytes. The maximum observed no-effect level (MONEL) for CCl4 in non-induced cells was 1.0 mM (LDH and K+). In induced cells, the MONEL was 0.25 mM (K+) and 0.5 mM (LDH). The MONEL for CHCl3 in non-induced cells was 5.0 mM (LDH and K+) and in induced cells was 0.5 mM (K+) and 1.0 mM (LDH). Phenobarbital pretreatment enhanced the toxicity of both CCl4 and CHCl3, alone and in combination. RSM analysis of the % initial K+ and % LDH for CCl4 and CHCl3 in combination in noninduced and induced cells showed a greater than additive interaction. The isolated hepatocyte model appears to be a promising system for evaluating the toxicity of chemical mixtures and predicting their in vivo effects.

Animals↗
PubMed1997

Suitability of test media containing EDTA for the evaluation of acute metal toxicity to Daphnia magna straus.

The acute toxicity of six metals [Hg, Cd, Cu, Zn, Cr(II), and Cr(VI)] to Daphnia magna neonates was evaluated using three different test media (Elendt M7, a complex medium containing EDTA; ASTM hard water and EEC, two simple media free of chelators). The EC50 values, at both 24 and 48 h, obtained for Zn, Cr(II), and Cr(VI) were similar in all of the media tested. Hg was more toxic in ASTM than in M7 and in EEC media. The toxicity of Cd and Cu was similar in ASTM and EEC media and higher when evaluated in M7 medium. Thus, M7 should be used only carefully for the toxicity evaluation of mixtures and effluents containing metals. It is recommended, however, that it be excluded from use in tests evaluating samples of unknown composition, or those known to contain Cu and Cd. For the metals tested in this study, a factor of five applied to each 48-h EC50 would be sufficient in order to attain the respective acute NOECs for immobility.

Animals↗