Adapting to changing attitudes towards food.
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Animal Husbandry↗
Biomedical subjects
R R Cook
Publications and source records attributed to R R Cook.
Nested case-control study of lung cancer among chemical workers.
A recent cohort mortality study of 19,608 male employees of a major Texas chemical production facility had suggested that they might be at higher risk of lung cancer compared with the male population of the United States or Texas but not with the male population of the five-county area in which they reside. An occupational exposure was a possible explanation for this pattern, and a nested case-control study was undertaken of the 308 lung cancer deaths observed between 1940 and 1981. Two control groups, one a decedent and the other a "living" series, were individually matched to cases one-for-one. Interviews were conducted with subjects or their next of kin to collect information on smoking and other potential confounders. These data were combined with employee work history records and industrial hygiene data to form the basis of the analyses. Traditional stratification methods and conditional logistic regression were employed to examine for effect modification and to control confounding. Statistically significant, positive and negative associations were found for assignment to several work areas within the facility. Suggestive associations were observed for exposure to sulfur dioxide and heat. These and additional associations are discussed relative to evidence from other studies.
Adult↗
Soft-tissue sarcoma: case-control study.
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Female↗
An update of mortality among chemical workers exposed to benzene.
Mortality was updated to the end of 1982 for 594 employees exposed to benzene who had been studied previously and for an additional 362 exposed workers not studied previously. Cause specific mortality comparisons were made using United States white male, age, and calendar year adjusted rates. Total mortality was observed to have been significantly below expectation, and this was particularly evident for deaths from accidental causes. Mortality from skin cancer was significantly raised, although there were no unusual or common characteristics among the affected individuals which would suggest a link with exposure to benzene. A non-significant excess of total deaths from leukaemia was noted based on four observed cases; however, all four were myelogenous leukaemias and this represented a significant excess in that subcategory. These and other deaths of possible interest are reviewed in detail. Analyses by work area, duration of exposure, and cumulative dose index did not show patterns suggestive of a causal association between exposure to benzene and any particular cause of death.
Adult↗
A case-control study of renal cancer mortality at a Texas chemical plant.
An in-plant case-control study of 26 renal cancer deaths was conducted to determine whether an occupational exposure may be related to an apparent increase in mortality from this disease observed among a sample of employees at a multiple process chemical production facility. None was found that explained the excess. Elevated odds ratios were identified for employment in the cell maintenance area of chlorine production and with those presumptive exposures considered to occur in this job, asbestos and caustic, but not chlorine. While an association between renal cancer and asbestos has been previously reported, an association with caustic, per se, is not consistent with prior observations made by others. Diminished risk estimates were observed for employment in magnesium production and for exposures in this process to sulfur dioxide and heat. Both the increased and decreased risks, while statistically significant, are based on small numbers of exposed subjects and may be spurious owing to the problem of multiple comparisons.
Adult↗
Mortality among a large cohort of chemical manufacturing employees.
Cause-specific mortality was surveyed among 19,608 male employees with 1 or more years of service between 1940 and 1980 at the Texas Operations of Dow Chemical U.S.A. Vital status was ascertained through 1980 for 97.3% of the cohort members, and death certificates were obtained for 96.4% of the 3,444 decedents. Mortality risks were found to vary, depending upon which of 3 population groups (United States, Texas, and local counties) was used for comparison, although significantly fewer than expected deaths from all causes was a common finding due to significant deficits in diabetes, diseases of the circulatory system, and cirrhosis of the liver. Significantly more deaths were from ill-defined conditions and cancers of unspecified sites. Lung cancer was significantly elevated in comparisons with the incidences in the United States and Texas, but not in comparison with those in the local counties. The influence of age at hire, period of hire, duration of employment, interval since entry into cohort, employment status, and two measures of social class--educational level and job category--were explored with the use of the Mantel-Haenszel method as adapted for a cohort study. Findings from these analyses are discussed in relation to the observations of other investigators and in the context of the possible impact of these findings on future studies of this work force.
Chemical Industry↗
Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II. Bovine chymotrypsin A alpha, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates.
The primary subsite specificities of human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin A alpha, and the protease from strain V-8 of Staphylococcus aureus have been mapped with a series of tripeptide thiobenzyl ester substrates of the general formula Boc-Ala-Ala-AA-SBzl, where AA represents one of 13 amino acids. In addition, the effects of a P2 Pro and P4 methoxysuccinyl and succinyl groups were investigated. In an attempt to introduce specificity and/or reactivity into the substrate Boc-Ala-Ala-Leu-SBzl(X), the 4-chloro-, 4-nitro-, and 4-methoxythiobenzyl ester derivatives were studied. Enzymatic hydrolyses of the substrates were measured in the presence of 4,4'-dithiobis(pyridine) or 5,5'-dithiobis(2-nitrobenzoic acid), which provided a highly sensitive assay method for free thiol. The thio esters were excellent substrates for the enzymes tested, and in many cases, the best substrates reported here have kcat/KM values higher than those reported previously. The best substrate for human leukocyte elastase was Boc-Ala-Pro-Nva-SBzl(Cl), which has a kcat/KM of 130 X 10(6) M-1 s-1. A very reactive rat mast cell protease substrate, Boc-Ala-Ala-Leu-SBzl(NO2), was also found. The S. aureus V-8 protease was the most specific enzyme tested since it hydrolyzed only Boc-Ala-Ala-Glu-SBzl. Substituents on the thiobenzyl ester moiety of Boc-Ala-Ala-Leu-SBzl resulted in decreased KM values with human leukocyte elastase and rat mast cell protease I when compared to the unsubstituted derivative.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Peptide thioesters and 4-nitroanilides as substrates for porcine pancreatic kallikrein.
A series of 14 4-nitroanilide substrates and 17 thioester substrates have been used to measure kinetic constants with porcine pancreatic kallikrein. All of the substrates have a P1 arginine residue. The 4-nitroanilide substrates consist of seven P2-glycine and seven P2-phenylalanine tripeptides. As expected from previous results, the phenylalanine series substrates were generally 100-fold 'better' than those in the glycine series. The S3 subsite was found to 'prefer' lysine or phenylalanine, whereas glutamic acid in this position was distinctly unfavourable. The thioester substrates consisted of various thioester derivatives of arginine as well as 12 dipeptides. These substrates exhibited kcat./Km values generally 1000 times higher than the P2-phenylalanine 4-nitroanilides. With the thioesters, a P2 phenylalanine or tryptophan residue yielded the best substrates, but some of the simple derivatives of arginine were nearly as good. A comparison of the kinetic constants of the thioester substrates between the porcine enzyme and human plasma kallikrein provides further evidence that these enzymes have a similar preference for bulky P2 residues, but otherwise are quite different enzymes. The thioester substrates are nearly as reactive as oxygen ester substrates such as acetylphenylalanylarginine methyl ester for the porcine enzyme [Levison & Tomalin (1982) Biochem. J. 203, 299-302; Fiedler (1983) Adv. Exp. Med. Biol. 156A, 263-274], and owing to the greater ease in assaying with the thioesters, they should find use in routine assays for the glandular kallikreins.
Anilides↗
Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates.
A series of 14 tripeptide 4-nitroanilide substrates of the type Z-AA-Gly-Arg-NA and Z-AA-Phe-Arg-NA where AA = Ala, Asn, Glu, Lys, Phe, Pro, or Ser were used to map the S3 subsite of several serine proteases involved in blood coagulation. The enzymes studied included bovine thrombin, factor IXa, factor Xa, factor XIa, human beta-factor XIIa (factor XIIa fragment), and activated bovine and human protein C. Kinetic constants (kcat, KM, and kcat/KM) for the enzymatic hydrolysis of the substrates by each enzyme were determined and used to compare the relative reactivities of the individual enzymes. Most of the enzymes reacted with all the substrates, although a few showed considerable specificity. Human beta-factor XIIa showed the highest reactivity of all the coagulation proteases studied and was also very substrate specific (kcat/KM ranged over 470-fold). The best substrate was Z-Lys-Phe-Arg-NA with kcat/KM = 140 000 M-1 s-1. Activated bovine protein C (best substrate = Z-Ser-Phe-Arg-NA), factor Xa (best substrate = Z-Glu-Gly-Arg-NA), and thrombin (best substrate = Z-Lys-Gly-Arg-NA) were the group of enzymes that showed next highest reactivity toward the substrates. Activated bovine protein C, thrombin, and factor Xa displayed relatively little substrate specificity. Activated human protein C (best substrate = Z-Ser-Phe-Arg-NA) and factor XIa (best substrate = Z-Glu-Gly-Arg-NA) are moderately reactive enzymes. Activated human protein C is an extremely specific enzyme since it has such a large range of kcat/KM values.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Kinetics of hydrolysis of peptide thioester derivatives of arginine by human and bovine thrombins.
Several peptide thioester substrates have been synthesized and tested with human thrombins (alpha, gamma, and nitrated), bovine thrombin, trypsin, and Factor X alpha beta. The substrates include various thioalkyl esters, thiobenzyl esters with substitution in the 4-position, substrates containing additional residues on the amino-terminal side of the scissile bond (P extended substrates) and one substrate containing additional residues on the carboxyl-terminal side (P' extended substrate). Neither the P nor the P' extensions resulted in significantly increased specificity; however, with one P extended substrate, D-Phe-Pro-Arg-SBzl, the KM with bovine thrombin (0.72 microM) was the second lowest KM yet reported. The results of this study underscore the importance of P vs. P' extension for thrombin substrates. The kinetic constants of the thiobenzyl esters were found to be little affected by the 4-position substitutions. A comparison of gamma-thrombin and nitrothrombin shows them to be quite similar kinetically, while both are significantly less reactive than alpha-thrombin. With these substrates, trypsin, bovine thrombin, and Factor X alpha beta have kcat/KM values in the approximate ratio of 35:10:1, respectively. The results presented here should be of value in the future design of reactive yet specific substrates for thrombin. The comparisons between the various enzymes could be helpful in clarifying the nature of their active sites.
Animals↗
Benzyl p-guanidinothiobenzoate hydrochloride, a new active-site titrant for trypsin and trypsin-like enzymes.
Benzyl p-guanidinothiobenzoate hydrochloride was synthesized and demonstrated to be useful for active-site titration of bovine trypsin, bovine thrombin, human lung tryptase, bovine activated protein C, human Factor XIIa fragment and bovine Factor Xa beta. The titration is based on rapid formation of a stable acyl-enzyme with a stoichiometric release of benzyl thiol. Thiol production is measured quantitatively by including 4,4'-dithiodipyridine in the reaction mixture and measuring the increase in absorbance at 324 nm. Ellman's reagent has also been successfully employed, allowing measurement at 410 nm. Unlike p-nitrophenyl p'-guanidinobenzoate, the thioester titrant reacts slowly with chymotrypsin A alpha thus eliminating interference by this enzyme in most titrations. Advantages of this reagent as a titrant include: flexibility in detection of the released thiol, selectivity between trypsin and chymotrypsin-like enzymes, minimal pH-dependence of the epsilon of the absorbing species, relative stability of the reagent under titration conditions, and high epsilon at pH 7.2 with either 4,4'-dithiodipyridine or Ellman's reagent. The reagent should prove useful as an alternative to p-nitrophenyl p'-guanidinobenzoate hydrochloride for the determination of active-site concentrations of the enzymes employed, as well as of other related enzymes.
Animals↗
Pattern makers mortality study.
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Colonic Neoplasms↗
Medical and morbidity surveillance findings among employees potentially exposed to TCDD.
Available medical and morbidity surveillance findings from 1976 to 1978 for two employee cohorts potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were compared with those of matched unexposed employees. The medical surveillance findings were derived from a screening programme offered to all active employees and included an analysis of various medical history questions and blood chemistry results. Group medical insurance claims served as the source of morbidity surveillance data and the period prevalence of selected diseases was analysed. Few significant differences between the exposed and unexposed were detected. Among the cohort of employees potentially exposed during the manufacture of 2,4,5-trichlorophenoxyacetic acid (2,4,5,-T), a significantly greater frequency of x-ray proved ulcer was reported and significantly more members of this group had diseases of the digestive system diagnosed. Such findings were absent in the more highly TCDD-exposed cohort engaged in 2,4,5-trichlorophenol production, making it unlikely that dioxin was a cause.
2,4,5-Trichlorophenoxyacetic Acid↗
The question of a cancer epidemic: a case study of Cherokee County, North Carolina.
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Disease Outbreaks↗
A case-control study of brain tumor mortality at a Texas Chemical plant.
A plant-based case-control study was undertaken to investigate a possible excess of brain tumor mortality identified at a Texas Chemical plant from a sample-based cohort study. Work histories and presumptive exposures of 28 former employees who had died of primary intracranial neoplasms were contrasted with those of two matched comparison groups in an effort to identify a possible etiologic agent. Because the sample-based cohort study suggested they might be at increased risk, those employees hired prior to 1945, those employed from one to four years and those employed for 20 or more years were studied separately. No statistically significant associations were found, although an elevated risk was suggested for employment in the machine shop prior to 1945 based on three exposed cases.
Adult↗
An investigation of brain tumors among chemical plant employees using a sample-based cohort method.
Using a modification of the traditional cohort mortality methodology, risk estimates of death due to brain tumors were calculated for production and nonproduction employees of Dow Chemical U.S.A., Texas Division. A total of 25 malignant, benign and unspecified brain tumors were identified using a geographically limited record-linkage process. Expected deaths were extrapolated from 1,666 white males in a 5% sample of the 1940 through 1977 total workforce. The resulting sample-based standardized mortality ratios (which were not evaluated for statistical significance) suggest, at most, only a slight increased risk of mortality from brain tumors for the overall time period. There was, however, a probable elevated risk associated with first employment prior to 1945. To date, diminished risk has been noted for those hired during subsequent years.
Adult↗
Survey of reproductive events of wives of employees exposed to chlorinated dioxins.
To determine whether paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or other polychlorinated dioxins might be associated with adverse pregnancy outcomes, an interviewer-administered questionnaire survey was conducted among wives of Dow Michigan Division employees in the Midland, Michigan, area who had been potentially exposed to dioxins. A control group consisted of wives of employees who had no dioxins exposure and whose hire dates were comparable to those of the men in the exposed group. A total of 737 conceptions, which resulted in 637 live births and 10 stillbirths and spontaneous abortions, were identified as having paternal exposure; 2031 conceptions, resulting in 1785 live births and 246 stillbirths and spontaneous abortions, were identified as having no paternal exposure to any isomer of dioxin. Odds ratios were calculated for dependent variables consisting of spontaneous abortions, stillbirths, infant deaths and several categories of congenital malformations. Trend analysis was performed for duration-of-paternal-exposure of 12 months or less, or more than 12 months. Overall, no statistically significant associations were found between any exposure and pregnancy outcome, either before or after stratification by pertinent sets of up to nine covariables.
Abnormalities, Drug-Induced↗
Case-control study of brain tumor deaths among employees at a chemical manufacturing plant.
Recent studies have reported an increased risk of death from primary intracranial neoplasms among employees in the petrochemical industry. One of them, a NIOSH/OSHA county-based case-control study, suggested a twofold risk for having ever been employed at the Texas Division of Dow Chemical U.S.A. Using the case-control approach, we compared 24 brain tumor cases among employees at this large, diverse chemical plant in Texas with two sets of age-, race-, and sex-matched controls to determine if a risk could be associated with job assignment in a particular process area, with presumptive exposure to a major process chemical, or with a number of other occupationally related and unrelated variables. Results implicated no specific area or chemical. The only significant findings were an elevated odds for being hired prior to 1950 and a negative correlation with employment greater than 10 years. Further, preliminary calculations of expected deaths from primary intracranial neoplasms among the employee cohort suggested there was no excessive risk.
Adult↗