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PubMed2005

Application and validation of approaches for the predictive hazard assessment of realistic pesticide mixtures.

In freshwater systems located in agricultural areas, organisms are exposed to a multitude of toxicologically and structurally different pesticides. For regulatory purposes it is of major importance whether the combined hazard of these substances can be predictively assessed from the single substance toxicity. For artificially designed multi-component mixtures, it has been shown that the mixture toxicity can be predicted by concentration addition (CA) in case of similarly acting substances and by independent action (IA), if mixtures are composed of dissimilarly acting substances. This study aimed to analyse whether these concepts may also be used to predictively assess the toxicity of environmentally realistic mixtures. For this purpose a mixture of 25 pesticides, which reflects a realistic exposure scenario in field run-off water, was studied for its effects on the reproduction of the freshwater alga Scenedesmus vacuolatus. The toxicity of the tested mixtures showed a good predictability by CA. This is consistent with the finding that the toxicity was dominated by a group of similarly acting photosystem II inhibitors, although the mixture included substances with diverse and partly unknown mechanisms of action. IA slightly underestimated the actual mixture toxicity. However, the EC(50) values that can be derived from each prediction, according to CA respectively IA, only differed by a factor of 1.3. The finding of such a small difference is partly explainable by the fact that only few components dominate the mixture scenario in terms of so-called toxic units (TUs). This connection is established by developing an equation that allows to calculate the maximum possible ratio between corresponding predictions of effect concentrations by IA and CA for any given ratio of the TUs of mixture components, irrespective of their individual concentration-response functions and independent from their mechanisms of action. To evaluate whether small quantitative differences between EC(50) values predicted by CA and IA are an exception or rather the rule for agricultural exposure scenarios, this calculation was applied on an additional set of 18 pesticide exposure scenarios that were taken from the literature. For these scenarios, EC(50) values predicted by IA can never exceed those predicted by CA by more than a factor of 2.5. The findings of this study support the view that CA provides a precautious but not overprotective approach to the predictive hazard assessment of pesticide mixtures under realistic exposure scenarios, irrespective of the similarity or dissimilarity of their mechanisms of action.

Animals↗
PubMed2004

Re-evaluation of metal bioaccumulation and chronic toxicity in Hyalella azteca using saturation curves and the biotic ligand model.

Bioaccumulation by Hyalella of all metals studied so far in our laboratory was re-evaluated to determine if the data could be explained satisfactorily using saturation models. Saturation kinetics are predicted by the biotic ligand model (BLM), now widely used in modelling acute toxicity, and are a pre-requisite if the BLM is to be applied to chronic toxicity. Saturation models provided a good fit to all the data. Since these are mechanistically based, they provide additional insights into metal accumulation mechanisms not immediately apparent when using allometric models. For example, maximum Cd accumulation is dependent on the hardness of the water to which Hyalella are acclimated. The BLM may need to be modified when applied to chronic toxicity. Use of saturation models for bioaccumulation, however, also necessitates the need for using saturation models for dose-response relationships in order to produce unambiguous estimates of LC50 values based on water and body concentrations. This affects predictions of toxicity at very low metal concentrations and results in lower predicted toxicity of mixtures when many metals are present at low concentrations.

Amphipoda↗
PubMed1985

Combined action of carbaryl and phenthoate on a freshwater fish (Channa punctatus bloch).

The toxic potencies of carbaryl and phenthoate were studied on a freshwater fish, Channa punctatus, by evaluating the percentage kill at different concentrations of exposure. To determine the combined action of these compounds, LC studies were performed by using carbaryl (C) and phenthoate (P) mixtures in the 1:3, 1:1, and 3:1 ratios. The 48-hr LC50 values obtained by calculating the data with probit method were 8.71 ppm for carbaryl and 0.473 ppm for phenthoate. Similar values on the mixtures were 0.717, 0.741, and 0.750 ppm for 1:3, 1:1, and 3:1, carbaryl:phenthoate mixtures. The toxicities of carbaryl and phenthoate have been discussed in relation to sensitivity of the species and their interaction with the target enzyme. Effectiveness of the joint action of carbaryl and phenthoate was determined by measuring three different parameters: the CTC value, the V value, and the CI value. This analysis showed that 3C:1P combination exerted marked synergism, 1C:1P exerted moderate synergism, and 1C:3P showed moderate antagonism.

Animals↗
PubMed1995

Halogenated aromatic hydrocarbons and toxicity equivalency factors (TEFs) from the public health assessment perspective.

The validity of the toxicity equivalency factors (TEFs) approach to predicting toxicity of mixtures was investigated on the basis of the public health risk assessment that had been posted for different groups of halogenated aromatic hydrocarbons. First, the minimal risk levels (MRLs) were derived based on the databases available for chlorinated dibenzo-p-dioxins (CDDs), chlorinated dibenzofurans (CDFs), and polychlorinated biphenyls (PCBs). The MRL values were then converted to 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD) toxicity equivalents (TEQs) and compared with each other. There was a good correlation between intermediate duration oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when expressed in TEQs (7 pg/kg/day and 15 pg/kg/day). Although the studies that served for derivation of these MRLs used different species (guinea pigs and rats, respectively), the toxicity endpoints (immunological and hepatic for TCDD and hepatic for 2,3,4,7,8-pentaCDF) were comparable. The hepatic effects were measured by the same techniques (blood chemistry and histopathology), ensuring similar sensitivity. However, there was a discrepancy between acute oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when they were expressed in TEQs (20 pg/kg/day and 500 pg/kg/day, respectively). The studies used for MRL derivation involved not only different species (mice and guinea pigs, respectively), the immunotoxicity endpoints were measured by techniques with different sensitivity (serum complement activity versus histopathology), making comparison difficult. Further calculations showed that the TEFs approach may be feasible for individual coplanar congeners of PCBs, but not for a mixture of Aroclors. Correlations presented here support the concept that the TEFs are valid only if specific criteria for their derivation are met (e.g., a broad database of information, consistency across endpoints, additivity for the effects, a common mechanism of action, etc.). In environmental exposure, the total toxicity of halogenated aromatic hydrocarbons is not necessarily the sum of the total individual congener toxicities because individual congeners compete for the same receptor; therefore, nonadditive behavior may occur.

Animals↗
PubMed2006

Synthesis of low and high chlorinated toxaphene and comparison of their toxicity by zebrafish (Danio rerio) embryo test.

Toxaphene, also known as camphechlor, is a persistent organochlorine pesticide of complex composition. It is technically produced by photochlorination of camphene with elemental chlorine gas under ultraviolet irradiation. In the present work, a novel, laboratory-scale synthesis using sulfuryl chloride as a chlorinating reagent is described. This approach allowed the degree of chlorination of the resulting mixtures to be arbitrarily adjusted by varying the reaction conditions. Both the compositions and the chlorine contents of the low- and high-chlorinated mixtures acquired using this method were similar to those of environmentally altered toxaphene and technical toxaphene, respectively. For comparison of these mixtures regarding toxicity, they were subjected to the zebrafish (Danio rerio) embryo test. Median effective concentrations (EC50s) were calculated based on the presence of lethal and nonlethal embryonic malformations. Surprisingly, low-chlorinated toxaphene, comprising compounds that also are present in environmentally transformed toxaphene, exhibited a twofold-higher toxicity (according to the EC50 for nonlethal effects) toward the test organisms compared with high-chlorinated toxaphene, the composition of which resembled that of the technical product. Although the effective concentrations in the embryo test were much higher than those in aquatic ecosystems burdened with toxaphene, the present results lead to the assumption that toxaphene is becoming more toxic during transformation in the environment. A decrease in the total amount of toxaphene during environmental breakdown would then be compensated for, at least in part, by the higher toxicity of weathered toxaphene in sediments, soils, and biota of contaminated ecosystems.

Animals↗
PubMed1981

Formation of gizzard erosion-inducing substance in heated casein-histidine mixture.

Formation of a toxic substance inducing gizzard erosion (GE) was examined by using mainly a casein-histidine mixture as a simple model of fish meal. When a casein-histidine mixture was heated at 135 degrees C for three or five hours or at 160 degrees C for one hour, it induced severe GE. Changes in pH of histidine solution seemed to have little effect on the production of the toxic substance. Addition of a heated mixture of 30 mg of histidine and 150 g of casein (per kg of diet) failed to induce GE. A mixture of 750 mg of histidine and 150 g of casein was enough to produce a maximal toxicity. A heated mixture of histidine and isolated soybean protein, ovalbumin or gluten induced severe GE. A heated mixture of gelatin and histidine had a somewhat milder toxicity. On the other hand, zein and yeast treated in the same way showed only a slight toxicity. Two kinds of pre-treatment of casein before the addition of histidine were proved to be ineffective to inhibit the formation of the toxic substance. The toxicity of heated casein-histamine was rather lower than that of heated casein-histidine. Studies were also made on releasing of the toxic substance from heated casein-histidine into the soluble fraction by acidic hydrolysis and precipitation of this substance at acidic pH.

Animals↗
PubMed1999

Effect of toxic metals on indigenous soil beta-subgroup proteobacterium ammonia oxidizer community structure and protection against toxicity by inoculated metal-resistant bacteria.

Contamination of soils with toxic metals is a major problem on military, industrial, and mining sites worldwide. Of particular interest to the field of bioremediation is the selection of biological markers for the end point of remediation. In this microcosm study, we focus on the effect of addition of a mixture of toxic metals (cadmium, cobalt, cesium, and strontium as chlorides) to soil on the population structure and size of the ammonia oxidizers that are members of the beta subgroup of the Proteobacteria (beta-subgroup ammonia oxidizers). In a parallel experiment, the soils were also treated by the addition of five strains of metal-resistant heterotrophic bacteria. Effects on nitrogen cycling were measured by monitoring the NH3 and NH4+ levels in soil samples. The gene encoding the alpha-subunit of ammonia monooxygenase (amoA) was selected as a functional molecular marker for the beta-subgroup ammonia oxidizing bacteria. Community structure comparisons were performed with clone libraries of PCR-amplified fragments of amoA recovered from contaminated and control microcosms for 8 weeks. Analysis was performed by restriction digestion and sequence comparison. The abundance of ammonia oxidizers in these microcosms was also monitored by competitive PCR. All amoA gene fragments recovered grouped with sequences derived from cultured Nitrosospira. These comprised four novel sequence clusters and a single unique clone. Specific changes in the community structure of beta-subgroup ammonia oxidizers were associated with the addition of metals. These changes were not seen in the presence of the inoculated metal-resistant bacteria. Neither treatment significantly altered the total number of beta-subgroup ammonia-oxidizing cells per gram of soil compared to untreated controls. Following an initial decrease in concentration, ammonia began to accumulate in metal-treated soils toward the end of the experiment.

Ammonia↗
PubMed1998

Engineering a recombinant Deinococcus radiodurans for organopollutant degradation in radioactive mixed waste environments.

Thousands of waste sites around the world contain mixtures of toxic chlorinated solvents, hydrocarbon solvents, and radionuclides. Because of the inherent danger and expense of cleaning up such wastes by physicochemical methods, other methods are being pursued for cleanup of those sites. One alternative is to engineer radiation-resistant microbes that degrade or transform such wastes to less hazardous mixtures. We describe the construction and characterization of recombinant Deinococcus radiodurans, the most radiation-resistant organism known, expressing toluene dioxygenase (TDO). Cloning of the tod genes (which encode the multicomponent TDO) into the chromosome of this bacterium imparted to the strain the ability to oxidize toluene, chlorobenzene, 3,4-dichloro-1-butene, and indole. The recombinant strain was capable of growth and functional synthesis of TDO in the highly irradiating environment (60 Gy/h) of a 137Cs irradiator, where 5x10(8)cells/ml degraded 125 nmol/ml of chlorobenzene in 150 min. D. radiodurans strains were also tolerant to the solvent effects of toluene and trichloroethylene at levels exceeding those of many radioactive waste sites. These data support the prospective use of engineered D. radiodurans for bioremediation of mixed wastes containing both radionuclides and organic solvents.

Chromosome Mapping↗
PubMed1998

[Poisoning with toxic plants in Curacao in 1766].

In the spring of 1766 a black supervisor in Curaçao was the victim of attempted poisoning by a black practitioner or curador, engaged by two persons caught stealing by the supervisor. Data on the case were preserved in a letter from the Curaçao director to the managers of the West-Indian Company in Amsterdam. In retrospect, the symptoms of the intoxication indicate that a similar mixture of toxic plants was used as described in 890 A.D. by the Arabic medical writer Wahshiya in his 'Book of Poisons': Calotropis procera and Pithecellobium unguis cati.

History, 18th Century↗
PubMed1989

Effect of a metal mixture in diet on the toxicokinetics and toxicity of cadmium, mercury and manganese in rats.

The purpose of this work was to determine whether a metal mixture added to diet influences the toxicokinetics and toxicity of some elements. The metal mixture (MM) used in these experiments was ash (slag) from a coal gasification plant. The effect of this mixture (5 percent in diet) on the toxicokinetic and on the acute or subchronic toxicity of Cd, Hg, Mn was determined in rats of different ages. Rats were exposed for five weeks in toxicokinetic and six weeks in acute toxicity experiments. Sucklings were exposed through their mothers, which received the MM in diet over the pregnancy and lactation period. In toxicokinetic studies, half of the animals additionally received Cd, Hg or Mn (100, 50 or 2000 ppm, respectively) in drinking water. In subchronic experiments, six-week-old albino rats of both sexes were given MM in the diet and Cd, Hg or Mn in drinking water for 16 weeks. In toxicokinetic studies, 115mCd, 203Hg or 54Mn were administered orally or intraperitoneally to mothers and pups. Exposure to MM had no effect on the absorption, retention and organ distribution of these elements determined six days after radioisotope administration. In acute toxicity studies, exposure to MM in diet had no effect on LD50 values obtained eight days after oral administration of Cd, Hg or Mn to rats of different ages. In subchronic experiments, the effect of individual metals (Cd, Hg or Mn) was similar in animals with and without simultaneous exposure to the metal mixture (only a slight potentiation of a few health-effect parameters of cadmium was noticed in some animals). It is concluded that oral exposure to MM in the diet had almost no effect on the toxicokinetics and toxicity of Cd, Hg and Mn. This could be explained by the low level or low bioavailability of elements from MM, by the metal-metal interaction within the mixture or by the choice of health effect indicators determined. These results are presented as one of the potential approaches for studying the health effect of a metal mixture as occurring in the environment.

Aging↗
PubMed2006

Toxicity and modulations of biomarkers in Xenopus laevis embryos exposed to polycyclic aromatic hydrocarbons and their N-heterocyclic derivatives.

Effects of a newly identified group of organic environmental pollutants of concern (N-heterocyclic derivatives of polycyclic aromatic hydrocarbons, NPAHs) were investigated using the 96 h FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Beside standard FETAX parameters (mortality, malformations), changes in several biochemical markers were studied as early signs of intoxication. Biomarkers included determination of glutathione (GSH) levels and lipid peroxidation as well as activities of important detoxification and antioxidant enzymes (glutathione-S-transferase, glutathione peroxidase, glutathione reductase). 1,10-Phenathroline was the most toxic of all tested compounds (96 h LC(50) = 4 microM). All tested NPAHs induced malformations in the frog embryos. The data suggest that the exposure to NPAHs can induce oxidative stress in amphibians; most biochemical markers were modulated at concentrations lower than those resulting in significant mortality. Results document mortality and teratogenicity of all studied NPAHs to amphibian embryos while no significant mortality, teratogenicity or modulations in biochemical markers could be observed with unsubstituted polycyclic aromatic hydrocarbons (PAHs) at concentrations up to their water solubility. This information along with the significantly greater solubility and thus bioavailability compared to their nonsubstituted parent compounds suggests that NPAHs could contribute significantly to the overall aquatic toxicity of mixtures of PAHs and their derivatives.

Abnormalities, Drug-Induced↗
PubMed1993

Relative potency of chlorinated dibenzo-p-dioxins (CDDs) in acute, subchronic and chronic (carcinogenicity) toxicity studies: implications for risk assessment of chemical mixtures.

This paper shows that the relative toxic potency of four chlorinated dibenzo-p-dioxins (CDDs) is similar in two species with different sensitivities (guinea pig, Sprague-Dawley rat). More importantly, it also demonstrates that the relative toxic potencies of these homologues are very similar for acute, subchronic and chronic dosing in the same species (rat). Furthermore, examination of different endpoints of toxicity (mortality, porphyria, carcinogenicity) suggests that the dose-responses for these diverse end-points after acute, subchronic, and chronic administration are very similar if not identical for tetra-CDD. Based on toxicokinetic and toxicodynamic considerations, a new, possibly generalizable rule (average tissue concentration x time = toxicity) is derived for CDDs. Implicit in the relative potency arguments of CDDs is the requirement of a practical threshold dose for all endpoints of toxicity including cancer.

Administration, Oral↗
PubMed1996

DNA damage induced in mouse tissues by organic wood preserving waste extracts as assayed by 32P-postlabeling.

Numerous wood preserving waste (WPW) sites in the United States pose genotoxic hazards. WPWs consist of complex mixtures containing toxic, including genotoxic, compounds which are derived from the preservatives coal tar creosote and pentachlorophenol (PCP) and other polychlorinated aromatics. The genotoxicity of WPW extracts, which has not been tested in mammals, cannot be evaluated on the basis of data for individual components because of possible compound interactions. Therefore, whole extracts need to be assayed. 32P-postlabeling represents a powerful tool to determine DNA adduct formation by complex genotoxic mixtures, such as cigarette smoke, diesel exhaust, and coke oven and foundry emissions in experimental animals and humans. In the present study, a mouse bioassay was used in combination with 32P-postlabeling to determine DNA adduct formation induced by hexane/acetone extracts of two samples from a WPW site. Female ICR mice were treated dermally with extract corresponding to 3 mg residue or vehicle control once per day for 2 days and killed 24 h later. Skin, lung, liver, kidney, and heart DNA preparations were assayed by nuclease P1-enhanced postlabeling. Adduct profiles were tissue-specific and displayed a multitude of non-polar DNA adducts with levels amounting to one adduct in 1.6 x 10(6) DNA nucleotides in skin (both extracts) and one adduct in 3.2 x 10(7) or 1.2 x 10(7) DNA nucleotides in liver (extract 1 or extract 2). Based on their chromatographic properties, these adducts appeared largely derived from polycyclic aromatic hydrocarbons (PAHs) present in the extracts. One of the major adducts was identified as the 32P-labeled derivative of the reaction product of 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7, 8,9,10-tetrahydrobenzo[a]pyrene (BPDE I) with N2 of deoxyguanosine. Total non-polar DNA adduct levels were highest in skin and lung, amounting to 17.4 and 24.0% of the skin values for extracts 1 and 2, respectively, in lung while the corresponding levels in liver were 5.0 and 12.6%. These results were in accord with the carcinogenic potencies of PAHs in these organs. Extract 2 induced higher adduct levels in internal organs, although its PAH concentrations were lower than those of extract 1, i.e. lung, liver, kidney, and heart had 1.4, 2.5, 1.9, and 1.7 times higher total adduct levels and 1.6, 3.3, 1.6, and 1.9 times higher benzo[a]pyrene adduct levels. With the exception of total adducts in lung, the differences between the two extracts were all significant, suggestive of compound interactions. The benzo[a]pyrene adduct levels in the five tissues correlated linearly with total adduct levels and thus represented a surrogate for the latter. Overall, the results suggest that DNA adducts in mouse tissues, as analyzed by 32P-postlabeling, are suitable biomarkers and dosimeters of the genotoxicity of WPW extracts.

Animals↗
PubMed2002

The genotoxicity of priority polycyclic aromatic hydrocarbons in complex mixtures.

Risk assessment of complex environmental samples suffers from difficulty in identifying toxic components, inadequacy of available toxicity data, and a paucity of knowledge about the behavior of geno(toxic) substances in complex mixtures. Lack of information about the behavior of toxic substances in complex mixtures is often avoided by assuming that the toxicity of a mixture is simply the sum of the expected effects from each mixture component, i.e. no synergistic or antagonistic interactions. Although this assumption is supported by research investigating non-genotoxic end-points, the literature describing the behavior of genotoxic substances in complex mixtures is sparse and, occasionally, contradictory. In this study, the results of polycyclic aromatic hydrocarbon (PAH) analyses on freshwater bivalves were used to prepare realistic mixtures containing up to 16 PAHs. The SOS genotoxicity of the mixtures and each component were then assessed in an effort to evaluate the additivity of PAH genotoxicity. At nominal PAH concentrations above 1 microg/ml, observed genotoxic responses were far lower than those predicted under the assumption of additivity. At nominal concentrations below 0.75 microg/ml, differences are smaller and occasionally negligible, indicating that the genotoxicity of unsubstituted homocyclic PAHs is additive or slightly less than additive. Other researchers who have investigated the mutagenicity, carcinogenicity, and DNA binding activity of mixtures containing unsubstituted homocyclic PAHs have also reported additive effects. Therefore, the mutagenic risk posed by simple, well-characterized mixtures of priority PAHs can reasonably be estimated as the sum of the risks posed by the mixture components. Current data indicate that less-than-additive effects likely result from saturation of metabolic pathways needed to activate mutagenic PAHs.

Animals↗
PubMed2005

Effects of the polycyclic aromatic hydrocarbon heterocycles, carbazole and dibenzothiophene, on in vivo and in vitro CYP1A activity and polycyclic aromatic hydrocarbon-derived embryonic deformities.

Heterocyclic derivatives of polycyclic aromatic hydrocarbons (PAHs) are often significant components of environmental contaminant mixtures; however, their contribution to the toxicity of these mixtures is not well characterized. These heterocycles commonly co-occur in PAH mixtures, which contain agonists for the aryl hydrocarbon receptor (AHR). Our goal for these studies was to explore the effects of two PAH heterocycles, carbazole (CB) and dibenzothiophene (DBT), alone and in combination with a PAH-type agonist for the AHR (beta-naphthoflavone [BNF]) on AHR-mediated cytochrome P4501A (CYP1A) activity and on fish embryotoxicity. Embryos of Fundulus heteroclitus were exposed to CB or DBT, with and without coexposure to BNE Carbazole alone slightly induced, whereas DBT alone slightly reduced, in ovo CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity compared to control values. However, exposure to CB or DBT reduced in ovo EROD activity in embryos coexposed to BNE Carbazole and DBT were characterized in vitro as noncompetitive CYP1A inhibitors. Carbazole and DBT enhanced the embryotoxicity of BNF, although neither compound was embryotoxic by itself. The co-occurrence of CB and DBT with PAH-type AHR inducers in contaminated ecosystems may increase the toxicity of PAH-type AHR agonists in these settings and may need to be considered when estimating the embryotoxicity of PAH mixtures.

Animals↗
PubMed2001

An evaluation of methods for calculating mean sediment quality guideline quotients as indicators of contamination and acute toxicity to amphipods by chemical mixtures.

Mean sediment quality guideline quotients (mean SQGQs) were developed to represent the presence of chemical mixtures in sediments and are derived by normalizing a suite of chemicals to their respective numerical sediment quality guidelines (SQGs). Mean SQGQs incorporate the number of SQGs exceeded and the degree to which they are exceeded and are used for comparison with observed biological effects in the laboratory or field. The current research makes it clear, however, that the number and type of SQGs used in the derivation of these mean quotients can influence the ability of mean SQGQ values to correctly predict acute toxicity to marine amphipods in laboratory toxicity tests. To determine the optimal predictive ability of mean SQGQs, a total of 18 different chemical combinations were developed and compared. The ability of each set of mean SQGQs to correctly predict the presence and absence of acute toxicity to amphipods was determined using three independent databases (n = 605, 2753, 226). Calculated mean SQGQ values for all chemical combinations ranged from 0.002 to 100. The mean SQGQ that was most predictive of acute toxicity to amphipods is calculated as SQGQ1 = ((sigma ([cadmium]/4.21 )([copper]/270)([lead]/ 12.18)([silver]/1.77)([zinc]/ 410)([total chlordane]/6)([dieldrin]/8)([total PAHoc]/1,800)([total PCB]/400))/9). Both the incidence and magnitude of acute toxicity to amphipods increased with increasing SQGQI values. To provide better comparability between regions and national surveys, SQGQ1 is recommended to serve as the standard method for combination of chemicals and respective SQGs when calculating mean SQGQs.

Animals↗
PubMed2003

Lack of developmental toxicity of D-003: a mixture of long-chain fatty acids in rats.

D-003 is a mixture of long-chain fatty acids isolated and purified from sugar cane wax, the major component of which is 1-octacosanoic acid and which possesses effective antiplatelet, antithrombotic and cholesterol-lowering effects. D-003 was suspended in 1% acacia gum solution, and given daily by gavage to rats at dose levels of 5, 100 and 1000 mg/kg/day on days 6 through 15 of gestation. Cyclophosphamide, serving as a positive control, was given at the dose of 50 mg/kg/day on day 15 of gestation. Evidence of maternal or developmental toxicity was not observed in the groups treated with D-003. Maternal clinical signs of toxicity were not observed and the analysis of initial body weight and the body weight gain during the treatment period was comparable among the groups treated with D-003 and control. As expected, cyclophosphamide caused both embryotoxic and teratogenic effects in rats. Meanwhile, no adverse effects on reproductive performance, or on embryonic or fetal development, including visceral and skeletal examination, were seen in any of the groups administered D-003. It is concluded that D-003 administered up to 1000 mg/kg/day did not induce any evidence of developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed1989

Problems in assessing the risks of mixtures of contaminants in drinking water.

In conducting risk assessments on drinking water contaminants, the U.S. Environmental Protection Agency (EPA) attempts to evaluate all available toxicity data to develop Health Advisory (HA) and Maximum Contaminant Level Goal (MCLG) values. The EPA often has grappled with the issues surrounding the toxicity of chemical mixtures, including radioactive contaminants, nitrate/nitrite, and trihalomethanes (THMs). In evaluating the toxicity of chemical mixtures, the EPA's immediate concern is whether the individual HA values and MCLGs are protecting public health when multiple contaminants are present in drinking water. Potential toxic interactions between drinking water contaminants are difficult to predict because experimental studies are generally performed only at high doses relative to environmental levels. Although the contamination of drinking water involves mixtures of contaminants, drinking water regulations are generally based on an assessment of the risks of individual contaminants. This paper discusses three issues of major concern to the EPA: the synergistic effects of solvent mixtures, vehicle effects in laboratory studies, and setting standards for essential trace nutrients where the absorption and/or toxicity are affected by an individual's nutritional status or other dietary components.

Animals↗