Toxicological assessment in Tetrahymena of intermediates in aerobic microbial transformation of toluene and p-xylene.
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Biomedical subjects
Publications and source records attributed to S E Bryant.
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The toxicities of 34 benzonitriles to Tetrahymena pyriformis have been measured. Structure-activity relationships indicate that for these compounds different mechanisms of toxic action are taking place dependent on the nature of the substituent. Benzonitrile itself, some halogenated and the toluene derivatives model as non-polar narcotics; more polar substituents model well as polar narcotics; whilst the nitro and aldehyde substituted benzonitriles, and compounds that may be metabolised to benzoquinone are shown to exhibit considerable excess toxicity and, thus, the probability is that they are acting by a specific mechanism of action. After the removal of two outliers, QSAR analysis reveals a significant three parameter equation, and confirms the importance of hydrophobicity and descriptors of reactivity for the comprehension and the prediction of the toxicity of the benzonitriles.
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Pentachlorophenol (PCP) is a widespread contaminate of soils and ground water throughout North America. Earlier studies have indicated that microbial biodegradation leads to the formation of intermediate metabolites which are more toxic than the parent compound. Microbial degradation is by three general pathways: dechlorination, methylation, and oxidation. The relative toxicity of PCP and 25 of its identified intermediates of microbial transformation was evaluated in the static Tetrahymena pyriformis population growth assay. Dechlorination of chlorophenols resulted in a decrease in toxicity because of a decrease in both hydrophobicity and reactivity. Moreover, dechlorination of chloroanisoles resulted in a decrease in toxicity due to a decrease in hydrophobicity. Since there was a decrease in reactivity, methylation of chlorophenols resulted in a decrease in toxicity. Oxidation of chlorophenols resulted in enhanced toxicity owing to increased reactivity and concomitant decreased hydrophobicity.
In an effort to explain the different platelet production capabilities of male and female mice, megakaryocyte and platelet indices were measured on castrated male and oophorectomized female C3H and BALB/c mice, along with suitable intact controls. In agreement with our previous work, intact male BALB/c mice had higher platelet counts and percent incorporation of sulfur 35 into platelet values than did intact female BALB/c mice. Also, both intact BALB/c and C3H male mice had higher platelet counts than their castrated counterparts. Fewer femoral megakaryocytes were found in intact BALB/c and C3H male mice than in their female counterparts (p less than 0.05), but only BALB/c male mice had larger megakaryocytes than BALB/c female mice (p less than 0.0005). Castration caused increased numbers and decreased sizes of megakaryocytes (p less than 0.05) in both strains of mice, but oophorectomy did not change the characteristics of megakaryocytes in these mice. In all treatment groups, C3H mice had megakaryocytes with higher average deoxyribonucleic acid content than did BALB/c mice (p less than 0.0005), that is, BALB/c mice had greater percentages of 8N and 16N megakaryocytes than did C3H mice, but C3H mice had higher proportions of 32N and 64N megakaryocytes than did BALB/c mice (p less than 0.05 to p less than 0.0005). Although a difference in megakaryocyte ploidy was not detected between intact male and intact female C3H mice, BALB/c female mice had elevated percentages of low ploidy classes (8N) when compared with BALB/c male mice (p less than 0.005). Intact male C3H mice had higher percentages of 16N megakaryocytes (p less than 0.05) than did their neutered counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)
The relative toxicity of 24 selected amines was evaluated in the 48 h Tetrahymena pyriformis static population growth impairment assay and compared with literature data for the 96 h Pimephales promelas flow-through mortality assay. Chemicals selected included normal and branched aliphatic primary amines, 4-position alkyl-substituted primary aromatic amines, as well as secondary and tertiary amines. Three amines were not toxic at saturation in the Tetrahymena system, whereas one amine was not toxic at saturation in the Pimephales system. Due to the aberrantly high toxicity of aniline observed in the Tetrahymena system, this chemical was not included in the analyses. For QSAR development, toxicity measured as log IGC50(-1) and log LC50(-1), respectively, was regressed against the log of the 1-octanol/water partition coefficient (log KOW). Both toxicity and hydrophobicity varied over five orders of magnitude. The model, log IGC50(-1) = 0.72(log KOW) - 1.64 (n = 20, r2 = 0.92) (1), was found to be a good predictor of toxicity in the Tetrahymena system. Similarly, the model, log LC50(-1) = 0.80(log KOW) - 1.80 (n = 23, r2 = 0.96) (2), was found to be a good predictor of toxicity in the Pimephales system. A comparison of Eqns (1) and (2) showed the models to be very similar. Therefore, as seen by the model, log LC50(-1) = 1.11(log IGC50(-1] - 0.01 (n = 20, r2 = 0.93) (3), a regression of the log toxicities gave a slope of one, an intercept of zero and a high correlation.
Young male rats were administered monocrotaline (40 mg/kg, s.c.) either after chemical sympathectomy with 6-hydroxydopamine (6-OHDA, 100 mg/kg), after serotonin synthesis inhibition with p-chlorophenylalanine (PCPA, 500 mg/kg), or after saline injection. Monocrotaline rats exhibited a loss of body weight, marked right ventricular hypertrophy (RVH), increased pulmonary vascular muscularization, but no change in left ventricular weight or hematocrit at 20 days post-monocrotaline. Pretreatment with 6-OHDA or PCPA reduced the degree of RVH; however, neither 6-OHDA nor PCPA pretreatment prevented or reduced the pulmonary vascular muscularization associated with monocrotaline. Control, 6-OHDA-, and PCPA-treated rats exhibited only changes in ventricular weights associated with changes in their body growth. Thus, the sympathetic nervous system and serotonergic mechanisms seem to be involved in the development of monocrotaline-induced right ventricular hypertrophy, but are not responsible for the pulmonary vascular lesion.