Regulatory toxicology and pharmacology : RTP
-
Regul. Toxicol. Pharmacol. · Oct 2009
Comparative StudyA study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure.
A clinical study, conducted in Germany, compared two methods of estimating exposure to cigarette smoke. Estimates of mouth level exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters for nicotine content. Estimates of smoke constituent uptake were achieved by analysis of corresponding urinary biomarkers: for nicotine; total nicotine equivalents (nicotine, cotinine, trans-3'-hydroxycotinine plus their glucuronide conjugates), for NNK; (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) plus glucuronide, for pyrene; 1-hydroxy pyrene (1-OHP) plus glucuronide and for acrolein; 3-hydroxylpropyl-mercapturic acid (3-HPMA) plus the nicotine metabolite cotinine in plasma and saliva. ⋯ Mean MLE estimates for nicotine, NNK and pyrene showed a dose response in line with ISO tar yield smoked, with 10 mg > 4 mg >1 mg, and for acrolein 10 mg> 4 mg > *1mg (where * indicates not significant at 95% confidence level). The mean exposure estimates from biomarkers for nicotine, NNK and acrolein also showed a dose response in line with ISO tar yield with 10 mg > 4 mg > 1 mg > NS, and for pyrene 10 mg > *4 mg> 1 mg> NS. This study shows that estimates of exposure obtained by filter analysis and biomarkers of exposure correlate significantly over a wide range of smoke exposures and that filter analysis may provide a simple and effective alternative to biomarkers for estimating smokers' exposure.
-
Regul. Toxicol. Pharmacol. · Aug 2009
Further evaluation of the utility of "sliding window" FASTA in predicting cross-reactivity with allergenic proteins.
FAO/WHO has recommended that IgE cross-reactivity between a transgenic protein and allergen be considered when there is greater than 35% identity over a sliding "window" of 80 amino acids. In a previous work, we evaluated the false positive and negative rates observed using the FAO/WHO criteria versus conventional, whole protein FASTA analyses [Ladics, G. S., Bannon, G. ⋯ Examination of the matches not recognized by the conventional search revealed two scenarios: (1) "true" false positives consisting of low statistical significance (as measured by E score, i.e., a measure of the potential random occurrence of aligned sequences used to evaluate the significance of an observed alignment) alignments not contained in the conventional FASTA outputs, and (2) above-threshold sliding window alignments that fell below the 35% identity threshold with the conventional FASTA analysis. Although some alignments within this second group were between regions of low sequence complexity, where there was little/no change in E score, the majority of the alignments displayed more significance (lower E scores) under the conventional FASTA algorithm, yet did not meet the threshold defined by FAO/WHO. These data question the utility of the FAO/WHO recommended sliding window FASTA compared to the traditional whole sequence FASTA analysis coupled with appropriate statistical analysis.
-
Regul. Toxicol. Pharmacol. · Feb 2009
ReviewEvaluation of potential human carcinogenicity of the synthetic monomer ethyl acrylate.
Ethyl acrylate (EA) is an acrylic monomer used in the manufacture of a variety of polymers and copolymers as components of many commercially important products. Human exposure to EA occurs primarily in the workplace via inhalation or dermal contact. In F344 rat and B6C3F(1) mouse studies of EA carcinogenicity conducted by the National Toxicology Program [National Toxicology Program, NTP, 1986. ⋯ This again supports a non-genotoxic MOA. In addition, the route and rate of EA exposure in rodents for forestomach neoplasia are irrelevant to potential human exposure, since humans do not have forestomach and are not exposed to EA by oral bolus. Thus, the weight of evidence indicates that the tumors produced in the rodent carcinogenicity studies arise from conditions that are irrelevant for human risk assessment.
-
Regul. Toxicol. Pharmacol. · Feb 2009
Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague-Dawley rats.
This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90mg/kg per day (n=10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. ⋯ These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10mg/kg/day for dams and 30mg/kg/day for embryo-fetal development.