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  • 1
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 28 (1985), S. 242-245 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: This paper presents benchmark (BMD) calculations and additional regression analyses of data from a study in which scores from 26 scholastic and psychological tests administered to 237 6- and 7-year-old New Zealand children were correlated with the mercury concentration in their mothers' hair during pregnancy. The original analyses of five test scores found an association between high prenatal mercury exposure and decreased test performance, using category variables for mercury exposure. Our regression analyses, which utilized the actual hair mercury level, did not find significant associations between mercury and children's test scores. However, this finding was highly influenced by a single child whose mother's mercury hair level (86 mgkg) was more than four times that of any other mother. When that child was omitted, results were more indicative of a mercury effect and scores on six tests were significantly associated with the mothers' hair mercury level. BMDs calculated from five tests ranged from 32 to 73 mgkg hair mercury, and corresponding BMDLs (95% lower limits on BMDs) ranged from 17 to 24 mgkg. When the child with the highest mercury level was omitted, BMDs ranged from 13 to 21 mgkg, and corresponding BMDLs ranged from 7.4 to 10 mgkg.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 8 (1988), S. 0 
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 pg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 pglkglday based on studies of a fisheating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled lo00 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 pglkglday and an MRL of 0.3 pglkglday.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: The T25 single-point estimate method of evaluating the carcinogenic potency of a chemical, which is currently used by the European Union (EU) and is denoted the EU approach, is based on the selection of a single dose in a chronic bioassay with an incidence rate that is significantly higher than the background rate. The T25 is determined from that single point by a linear extrapolation or interpolation to the chronic dose (in mg/kg/day), at which a 25% increase in the incidence of the specified tumor type is expected, corrected for the background rate. Another method used to obtain a carcinogenic potency value based on a 25% increase in incidence above the background rate is the estimation of a T25 derived from a benchmark dose (BMD) response model fit to the chronic bioassay data for the specified tumor type. A comparison was made between these two methods using 276 chronic bioassays conducted by the National Toxicology Program. In each of the 2-year bioassays, a tumor type was selected based on statistical and biological significance, and both EU T25 and BMD T25 estimates were determined for that end point. In addition, simulations were done using underlying cumulative probability distributions to examine the effect of dose spacing, the number of animals per dose group, the possibility of a dose threshold, and variation in the background incidence rates on the EU T25 and BMD estimates. The simulations showed that in the majority of cases the EU T25 method underestimated the true T25 dose and overestimated the carcinogenic potency. The BMD estimate is generally less biased and has less variation about the true T25 value than the EU estimate.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 8 (1988), S. 0 
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Twenty-three chemicals were selected for comparison of the carcinogenic potencies estimated from epidemiological data to those estimated from animal carcinogenesis bioassays. The chemicals were all those for which reasonably strong evidence of carcinogenicity could be found in humans or animals and for which suitable data could be obtained for quantifying carcinogenic potencies in both humans and animals. Many alternative methods of analyzing the bioassay data were investigated. Almost all of the methods yielded potency estimates that were highly correlated with potencies estimated from epidemiological data; correlations were highly statistically significant (p 〈 0.001), with the corresponding correlation coefficients ranging as high as 0.9. These findings provide support for the general use of animal data to evaluate carcinogenic potential in humans and also for the use of animal data to quantify human risk.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Publishing, Inc.
    Risk analysis 24 (2004), S. 0 
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Estimates of the lifetime-absorbed daily dose (LADD) of acrylamide resulting from use of representative personal-care products containing polyacrylamides have been developed. All of the parameters that determine the amount of acrylamide absorbed by an individual vary from one individual to another. Moreover, for some parameters there is uncertainty as to which is the correct or representative value from a range of values. Consequently, the parameters used in the estimation of the LADD of acrylamide from usage of a particular product type (e.g., deodorant, makeup, etc.) were represented by distributions evaluated using Monte Carlo analyses.(1–4) From these data, distributions of values for key parameters, such as the amount of acrylamide in polyacrylamide, absorption fraction, etc., were defined and used to provide a distribution of LADDs for each personal-care product. The estimated total acrylamide LADD (across all products) for males and females at the median, mean, and 95th percentile of the distribution of individual LADD values were 4.7 × 10−8, 2.3 × 10−7, and 7.3 × 10−7 mg/kg/day for females and 3.6 × 10−8, 1.7 × 10−7, and 5.4 × 10−7 mg/kg/day for males. The ratio of the LADDs to risk-specific dose corresponding to a target risk level of 1 × 10−5, the acceptable risk level for this investigation, derived using approaches typically used by the FDA, the USEPA, and proposed for use by the European Union (EU) were also calculated. All ratios were well below 1, indicating that all the extra lifetime cancer risk from the use of polyacrylamide-containing personal-care products, in the manner assumed in this assessment, are well below acceptable levels. Even if it were assumed that an individual used all of the products together, the estimated LADD would still provide a dose that was well below the acceptable risk levels.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1539-6924
    Keywords: Benchmark ; mercury ; risk assessment ; epidemiology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper presents benchmark (BMD) calculations and additional regression analyses of data from a study in which scores from 26 scholastic and psychological tests administered to 237 6- and 7-year-old New Zealand children were correlated with the mercury concentration in their mothers' hair during pregnancy. The original analyses of five test scores found an association between high prenatal mercury exposure and decreased test performance, using category variables for mercury exposure. Our regression analyses, which utilized the actual hair mercury level, did not find significant associations between mercury and children's test scores. However, this finding was highly influenced by a single child whose mother's mercury hair level (86 mg/kg) was more than four times that of any other mother. When that child was omitted, results were more indicative of a mercury effect and scores on six tests were significantly associated with the mothers' hair mercury level. BMDs calculated from five tests ranged from 32 to 73 mg/kg hair mercury, and corresponding BMDLs (95% lower limits on BMDs) ranged from 17 to 24 mg/kg. When the child with the highest mercury level was omitted, BMDs ranged from 13 to 21 mg/kg, and corresponding BMDLs ranged from 7.4 to 10 mg/kg.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 7 (1990), S. 1294-1297 
    ISSN: 1573-904X
    Keywords: fluoropyrimidine ; cytotoxicity ; L1210 cells ; 5-fluorouracil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Cultured L1210 murine lymphocytic leukemia cells were used to compare metabolic activation and cytotoxicity of 5-fluorouracil (FU), Ftorafur (FT), and three novel FU-sulfur analogues. These analogues, l-(2′-tetrahydrothienyl)-5-fluorouracil (FUS), l-(2′-tetrahydrothienyl)-5-fluorouracil-l′-oxide (FUSO), and 1-(2′-tetrahydrothienyl)-5-fluorouracil-l′-l′-dioxide (FUSO2), have yet to be fully evaluated for potential therapeutic value based on in vitro cytotoxicity. The role of these FU analogues as prodrugs was evaluated by comparing metabolism of normal pyrimidine pathways and activation by hepatic mixed function oxidases (MFO). Significant differences in biochemical activity and cytotoxicity were measured between FU and FU analogues. FU and FU analogues were cytotoxic to L1210 cells (63–92% growth inhibition of 100 µM concentrations after 72 hr of incubation). However, at equimolar concentrations cytotoxicity of the FU analogues after MFO activation (56–66% growth inhibition) was greater than FU (47% growth inhibition). Hypoxanthine, a purine precursor, did not significantly alter fluoropyrimidine cytotoxicity with or without MFO. Thymidine and uridine, pyrimidine precursors, reduced FT and FUS cytotoxicities in the presence (27, 40%) and absence (25, 15%) of MFO but did not modify FU, FUSO, or FUSO2 cytotoxicities.
    Type of Medium: Electronic Resource
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