Murray and Associates

San Jose, CA, United States

Murray and Associates

San Jose, CA, United States
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Jay Murray F.,Murray and Associates | Gray T.M.,American Petroleum Institute | Roberts L.G.,Chevron | Roth R.N.,Roth Toxicology Consulting | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2013

To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary. © 2013 Elsevier Inc.


Gray T.M.,American Petroleum Institute | Simpson B.J.,Simpson Toxicology Consulting | Nicolich M.J.,COGIMET | Murray F.J.,Murray and Associates | And 3 more authors.
Regulatory Toxicology and Pharmacology | Year: 2013

In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG. 1The Petroleum HPV Testing Group (PHPVTG) is an unincorporated group of manufacturers affiliated by contractual obligation to fund a voluntary data disclosure and toxicity testing program on certain petroleum-related chemical substances in response to EPA's HPV Challenge Program. The American Petroleum Institute (API) manages the Group's activities.1) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥approximately 650. °F (343. °C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS. © 2012.


Murray F.J.,Murray and Associates | Roth R.N.,Roth Toxicology Consulting | Nicolich M.J.,COGIMET | Gray T.M.,American Petroleum Institute | Simpson B.J.,Simpson Toxicology Consulting
Regulatory Toxicology and Pharmacology | Year: 2013

In response to the US EPA HPV Challenge Program, this study was conducted to: (1) evaluate the relationship between PAC content and the developmental toxicity of high-boiling petroleum substances (HBPS) and (2) develop mathematical models to predict the developmental toxicity of similar untested substances based on their aromatic ring class (ARC) profiles. For this investigation, 68 developmental toxicity studies were reviewed. The ARC models relied on data from 21 rat dermal developmental toxicity studies conducted with similar experimental designs to ensure a consistent data set for comparison. The most sensitive general endpoints of developmental toxicity (i.e., decreased fetal survival and growth) were chosen for modeling. The ARC models demonstrated a strong correlation between the predicted vs. observed values for specific sensitive endpoints of these developmental toxicities (percent resorptions, r= 0.99; live fetuses per litter, r= 0.98; fetal body weight, r= 0.94). Such associations provide a promising approach for predicting the developmental toxicity of untested HBPS. Efforts to corroborate the ARC models using test substances that were not used to build the ARC models produced mixed results, and further development and refinement of the ARC models is recommended before they can be reliably applied to all HBPS. © 2013 Elsevier Inc.


Nicolich M.J.,COGIMET | Simpson B.J.,Simpson Toxicology Consulting | Jay Murray F.,Murray and Associates | Roth R.N.,Roth Toxicology Consulting | Gray T.M.,American Petroleum Institute
Regulatory Toxicology and Pharmacology | Year: 2013

The repeat-dose and developmental toxicities of certain petroleum refinery streams are related to their polycyclic aromatic compound (PAC) content (Feuston et al., 1994). Building on this foundation, and working within the context of the US EPA High Production Volume (HPV) Chemical Challenge Program, we:. (1) characterized relationships between PAC content and repeat-dose and developmental toxicities of high boiling petroleum substances (HBPS), and. (2) developed statistical models that can be used to predict critical effects of similar untested substances. Data from 39 dermal toxicity studies of HBPS were used to develop statistical models to predict the dose-response relationships between the weight percent concentration of each of their 1-7 aromatic ring classes and 4 repeat-dose and 3 developmental endpoints (absolute thymus weight, hemoglobin count, platelet count, liver to body weight, live fetus count, fetal weight, and percent resorptions). The correlations between the observed and model-predicted values are >0.90. The predictive ability of the models was tested via a series of evaluation or corroboration methods. As is shown in the paper, using only compositional data of untested HBPS, the models can be used to predict the effect at a given dose or the dose that causes an effect of a stipulated magnitude. © 2012.


Roth R.N.,Roth Toxicology Consulting | Simpson B.J.,Simpson Toxicology Consulting | Nicolich M.J.,COGIMET | Murray F.J.,Murray and Associates | Gray T.M.,American Petroleum Institute
Regulatory Toxicology and Pharmacology | Year: 2013

A study was undertaken within the context of the U.S. EPA HPV Chemical Challenge Program to (1) characterize relationships between PAC content and repeat-dose toxicities of high-boiling petroleum substances (HBPS) and (2) develop statistical models that could be used to predict the repeat-dose toxicity of similar untested substances. The study evaluated 47 repeat-dose dermal toxicity and 157 chemical compositional studies. The four most sensitive endpoints of repeat-dose toxicity were platelet count, hemoglobin concentration, relative liver weight and thymus weight. Predictive models were developed for the dose-response relationships between the wt.% concentration of each of seven ring classes of aromatic compounds (the "ARC profile") and specific effects, with high correlations (r = 0.91-0.94) between the observed and model-predicted data. The development of the mathematical models used to generate the results reported in this study is described by Nicolich et al. (2013). Model-generated dose-response curves permit the prediction of either the effect at a given dose or the dose that causes a given effect. The models generate values that are consistent with other standard measures. The models, using compositional data, can be used for predicting the repeat-dose toxicity of untested HBPS. © 2013 Elsevier Inc.


Jay Murray F.,Murray and Associates | Tyl R.W.,Rti International | Sullivan F.M.,Harrington House | Tiwary A.K.,Chevron | Carey S.,International Molybdenum Association IMOA
Reproductive Toxicology | Year: 2014

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2. μg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40. mg. Mo/kg. bw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40. mg. Mo/kg. bw/day, the highest dose tested. © 2014 The Authors.


Roberts L.G.,Chevron | Gray T.M.,American Petroleum Institute | Trimmer G.W.,ExxonMobil | Parker R.M.,Princeton Research Center | And 3 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

Gasoline-vapor condensate (BGVC) or condensed vapors from gasoline blended with methyl t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME) diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for developmental toxicity in Sprague-Dawley rats exposed via inhalation on gestation days (GD) 5-20 for 6h/day at levels of 0 (control filtered air), 2000, 10,000, and 20,000mg/m3. These exposure durations and levels substantially exceed typical consumer exposure during refueling (<1-7mg/m3, 5min). Dose responsive maternal effects were reduced maternal body weight and/or weight change, and/or reduced food consumption. No significant malformations were seen in any study. Developmental effects occurred at 20,000mg/m3 of G/TAME (reduced fetal body weight, increased incidence of stunted fetuses), G/TBA (reduced fetal body weight, increased skeletal variants) and G/DIPE (reduced fetal weight) resulting in developmental NOAEL of 10,000mg/m3 for these materials. Developmental NOAELs for other materials were 20,000mg/m3 as no developmental toxicity was induced in those studies. Developmental NOAELs were equal to or greater than the concurrent maternal NOAELs which ranged from 2000 to 20,000mg/m3. There were no clear cut differences in developmental toxicity between vapors of gasoline and gasoline blended with the ether or alcohol oxygenates. © 2014 Elsevier Inc.


Roberts L.G.,Chevron | Gray T.M.,American Petroleum Institute | Marr M.C.,Rti International | Tyl R.W.,Rti International | And 3 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5-17 at levels of 0, 2000, 10,000, and 20,000mg/m3. Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m3 of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m3) and ectopia cordis (1 fetus at 2000mg/m3; 2 fetuses/1 litter at 10,000mg/m3). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5-16 and an additional group exposed to 30,000mg/m3 from GD 5-10. An increased incidence of cleft palate was observed at 30,000mg/m3 G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m3. The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m3, 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study. © 2014 The Authors.


Murray F.J.,Murray and Associates | Sullivan F.M.,Harrington House | Tiwary A.K.,Chevron | Carey S.,International Molybdenum Association
Regulatory Toxicology and Pharmacology | Year: 2014

This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90days at dose levels of 0, 5, 17 or 60mgMo/kgbw/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416. The overall no-observed-adverse-effect level was 17mgMo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60mgMo/kgbw/day. No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level. No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight. Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60mgMo/kgbw/day. In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17mgMo/kgbw/day, respectively. © 2013 The Authors.


Murray F.J.,Murray and Associates
Food and Chemical Toxicology | Year: 2011

4-Methylimidazole (4-MEI) is found in a wide array of food products. The National Toxicology Program (NTP) recently conducted a two-year feeding cancer bioassay of 4-MEI in B6C3F1 mice and F344/N rats. In rats, NTP found "equivocal evidence of carcinogenic activity" in females based on increased incidences of mononuclear cell leukemia and "no evidence of carcinogenic activity" in males. However, dose-related, statistically significant decreases in multiple tumors were observed in both male and female rats exposed to 4-MEI in the NTP bioassay. For example, 4-MEI was associated with a 25-fold decrease in the incidence of mammary tumors among high dose females. NTP noted briefly that the decreases in certain tumors, including mammary tumors, were greater than could be attributed to body weight alone. The present paper provides a more detailed evaluation of the evidence that 4-MEI exhibits tumor preventive activity in the rat based upon the results of the NTP bioassay. Reduced body weight offers a partial explanation for the reduction in tumors, but does not appear to be the primary cause of the decreased tumor incidences, indicating that 4-MEI itself may possess an ability to prevent tumor formation. © 2010 Elsevier Ltd.

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