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This article is from Experimental and Therapeutic Medicine , volume 7 . Abstract Adriamycin (ADR), an antineoplastic antibiotic used in cancer therapy, is associated with toxicity to vital organs with long-term use. A nutrient mixture (NM) has previously been shown to exhibit a broad spectrum of therapeutic properties. The aim of the present study was to determine whether the NM is useful for preventing ADR-induced hepatic and nephric toxicity. Six-week-old male BALB/c mice were divided into four groups of six animals each. Groups A and C were fed a regular diet for three weeks and groups B and D were fed a diet supplemented with 1% NM. After three weeks, the mice in groups C and D received 20 mg/kg body weight ADR intraperitoneally, while those in groups A and B received saline alone. Animals were sacrificed after 24 h, blood samples were collected and serum was obtained for clinical chemistry. Organs were also excised and weighed. Administration of ADR to group C (control diet) resulted in a marked increase in hepatic alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase levels and renal blood urea nitrogen, creatinine and uric acid serum markers. However, in group D (NM 1% diet), the serum markers were comparable with the levels of group A and B. Therefore, the results indicate that NM has the potential to protect against ADR-induced hepatic and nephric damage.

The purpose of the study was to determine the toxicity to animals of a mixture of the insect repellents Deet and AI3-37220, and to assess its dermal effects in humans. A mixture of the insect repellents Deet and AI3-37220 in 95 percent alcohol (25:25:50) did not cause primary skin irritation nor sensitization in animals, was moderately toxic by the oral route but was essentially nontoxic dermally. In humans, no skin irritation nor sensitization was produced by the repellents mix. The toxicity of the repellents mixture did not exceed the toxicities of the individual components. It is recommended that repellents mixtures containing up to 25 percent each of Deet and AI3-37220 undergo advanced entomological testing in humans. Based upon the known eye irritation potential of the individual components, it is recommended that mixtures of Deet and AI3-37220 in ethyl alcohol be used with caution around the eyes and mucosa.

This article is from Experimental and Therapeutic Medicine , volume 7 . Abstract Amiodarone (Amio), a potent anti-arrhythmic drug, is associated with life-threatening pulmonary toxicity involving fibroses and inflammation. A unique nutrient mixture (NM) consisting of lysine, proline, ascorbic acid, N-acetyl cysteine and green tea extract has previously been shown to exhibit a broad spectrum of pharmacological, therapeutic, cardiovascular and chemopreventive properties. The present study was undertaken to determine whether the NM exhibits preventive effects on Amio-induced cardiac toxicity. Six-week-old male BALB/c mice were divided into four groups (A–D) of six animals per group. Mice in groups A and C were fed a regular diet for three weeks, while the diets of the mice in groups B and D were supplemented with 1% NM during that period. After three weeks, the mice in groups C and D received daily Amio injections of 50 mg/kg body weight intraperitoneally for 4 days, whilst those in groups A and B received saline alone. At 24 h after the final dose, mice were sacrificed, blood was withdrawn and serum was collected for clinical chemistry of the heart enzymes creatine phosphokinase (CPK) and aspartate aminotransferase (AST). In addition, livers, kidneys, hearts and lungs were excised and weighed. No significant differences in weight gain were identified among the groups and liver, kidney, heart and lung weights were comparable in all four groups. Administration of Amio to group C resulted in a significant increase in serum CPK levels, whereas in NM-fed group D, the CPK levels were comparable to those in the saline injection groups, A and B. Amio administration also resulted in a significant increase in serum AST levels in group C, but not in the group D animals which exhibited similar levels to those of groups A and B. Therefore, the results indicate that NM has the potential to protect against Amio-induced cardiac toxicity.

This article is from PLoS ONE , volume 9 . Abstract Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails.

This volume was digitized and made accessible online due to deterioration of the original print copy.

While many studies on the toxicity of pesticides looked at the effects of a higher mean temperature, effects of the realistic scenario of daily temperature variation are understudied. Moreover, despite the increasing interest for the toxicity of pesticide mixtures how this is influenced by temperature has been largely ignored. We tested whether daily temperature variation (DTV) magnifies the toxicity of two pesticides with a different mode of action, the organophosphate pesticide chlorpyrifos (CPF) and the biopesticide Bacillus thuringiensis var. israelensis (Bti), and of their mixture in the vector mosquito Culex pipiens. Single exposure to CPF and Bti increased mortality and reduced female development time, and exposure to CPF also increased female wing length. DTV was not lethal and did not change the toxicity of the individual pesticides. Yet, a key novel finding was that high DTV increased the mortality of the mixture by changing the interaction between both pesticides from additive to synergistic. Given that in nature daily temperature variation is omnipresent, this is important both for vector control and for ecological risk assessment. The higher toxicity of the mixture at high DTV compared to the typically used constant test temperatures in the laboratory urges caution when evaluating the environmental impact of pesticide mixtures.

An approach has been developed to estimate binary mixture toxicity by testing one chemical (A) with a series of other chemicals (B) and in an A-B combination (MX). We collected data on A-alone, B-alone and the MX for a series of chemical Bs (each A, B and MX is a data set). For each data set, mixture toxicity was evaluated against the concentration addition (CA) and independent action (IA) models of mixture toxicity. For the series, the data was then used to develop multiple linear regression equations as a way to estimate mixture toxicity for a B chemical that has not been tested with A.

An approach has been developed to estimate binary mixture toxicity by testing one chemical (A) with a series of other chemicals (B) and in an A-B combination (MX). We collected data on A-alone, B-alone and the MX for a series of chemical Bs (each A, B and MX is a data set). For each data set, mixture toxicity was evaluated against the concentration addition (CA) and independent action (IA) models of mixture toxicity. For the series, the data was then used to develop multiple linear regression equations as a way to estimate mixture toxicity for a B chemical that has not been tested with A.

The purpose of the study was to determine the toxicity to animals of a mixture of the insect repellents Deet and A13-37220, and to assess its dermal effects in humans. A mixture of the insect repellents Deet and A13-37220 in 95 percent alcohol (25:25:50) did not cause primary skin irritation nor sensitization in animals, was moderately toxic by the oral route but was essentially nontoxic dermally. In humans, no skin irritation nor sensitization was produced by the repellents mix. The toxicity of the repellents mixture did not exceed the toxicities of the individual components. It is recommended that repellents mixtures containing up to 25 percent each of Deet and AI3-37220 undergo advanced entomological testing in humans. Based upon the known eye irritation potential of the individual components, it is recommended that mixtures of Deet and A13-37220 in ethyl alcohol be used with caution around the eyes and mucosa.

The DoD requires the development of toxicity profiles for chemical substitute candidates proposed to replace ozone depleting substances such as chloro- and fluorocarbons and halons. A 93:7 mixture of perfluoro-2-butene and 1-bromopropane was identified as a possible replacement candidate for ozone-depleting fire extinguishants An acute inhalation toxicity test utilizing male and female Fischer 344 rats was performed on this test material. No deaths occurred in any of the rats exposed to 5.3 mg/L of the 93:7 perfluoro-2-butene and 1-bromopropane mixture. Body weights of male and female rats during the subsequent 14-day observation period were unaffected by treatment. The test material did not produce acute toxicity via the inhalation route.

The DOD requires the development of a toxicity profile for chemical substitute candidates, that have little or no ozone depleting potential, to replace ozone depleting substances such as chloro-and bromofluorocarbons (halons). A 9:1 mixture of 1,1,1,3,3,3-hexafluoropropane (HFC-236fa) and 1-bromopropane (BP) was identified as a possible replacement candidate for ozone-depleting fire extinguishants. An acute inhalation toxicity assessment utilizing male and female Fischer 344 rats was performed on this mixture. No deaths occurred in any of the rats exposed to 5.09 mg/L of the 9:1 HFC-236fa and BP mixture. Body weights of male rats during the subsequent 14-day observation period appeared unaffected by treatment. Female rat mean body weights averaged <3 g from their initial body weights at the end of the postexposure period, but no signs of toxic stress were observed in any animals. The 9:1 mixture of HFC-236fa and BP did not produce acute toxicity via the inhalation route.

The acute toxicity of TNT, RDX, LAP (1.6 TNT/1.0 RDX), and/or LAP(I) (photolyzed LAP: 0.032 TNT/1.0 RDX, 10% undegraded RDX) was determined in mammalian species. In male and female rats, respectively, the acute oral LD50s were: TNT, 1320 and 794 mg/kg; RDX, 71 and about 70 mg/kg; and LAP, 574 and 594 mg/kg or lower, depending on particle size. In male and female mice, respectively, the LD50s were: TNT, 660 mg/kg (both sexes); RDX, < 75 and 86 mg/ kg; and LAP947 and 1131 mg/kg. LAP(I) was examined in mice only; the acute oral LD50s in males and females were: 585 and 684 mg/kg, respectively. LAP and LAP(I) produced conjunctivitis, iritis, and/or corneal opacity in rabbit eyes; the irritation was not totally reversed in unwashed eyes after 7 days and longer. In in vitro microbial assays using microsomal activation (Ames Test), TNT was mutagenic. LAP was also mutagenic, and photolysis increased its mutagenicity. In contrast, in vivo cytogenetics studies on rat bone marrow extracts failed to detect an effect of either TNT or LAP on somatic cells. The effects of repeated oral administration of TNT and of LAP were determined in 90-day studies in dogs, rats, and mice. Observations common to the three species treated with either test material were depressed body weight and/or weight gain and food intake, mild to moderate hemolytic anemia, enlarged spleens.