Clinical Director, Touro University Nevada College of Osteopathic Medicine
Similar results were seen in these in vivo studies using peripheral red blood cells (Allen et al arthritis medication nsaid discount 60 mg etoricoxib mastercard. The liver is the other site of tumor response arthritis in dogs early signs quality 120mg etoricoxib, but this tissue has not been examined in in vivo chromosomal instability assays in the mouse arthritis pain how to treat order etoricoxib 90mg with visa. Results from dichloromethane chromosomal instability assays (in vivo and in vitro) arthritis flare up in dogs generic 90 mg etoricoxib free shipping, by species Route, exposure, durationa Test system, assay In vivo, mouse (B6C3F1 unless otherwise noted) Results Reference Allen et al. The type of tissue specificity that was seen with the chromosomal instability studies was also seen with the mouse in vivo indicator assays, with predominately negative results at sites other than lung or liver, and in the rodents other than mice (Table 4-36). With respect to the third key event in the hypothesized mutagenic mode of action, mutagenic data in critical genes leading to the initiation of dichloromethane-induced tumors are not available. In in vivo assays of mutations in tumor suppressor genes and oncogenes, similar frequencies of activated H-ras genes and inactivation of the tumor suppressor genes, p53 and Rb1, in the liver tumors were seen in nonexposed and dichloromethane-exposed B6C3F1 mice (Devereux et al. There were too few lung tumors (n = 7) in controls to support the comparison of mutation patterns between exposed and nonexposed tumors. The database for dichloromethane provides support along each of these lines: 1) in vivo evidence of chromosomal mutations (chromosomal aberrations and micronuclei) in the mouse lung and peripheral red blood cells in the absence of evidence of cytoxicity; these endpoints have not been examined in the liver. These observations were not seen in the mouse bone marrow, a much more limited site in terms of degree of dichloromethane metabolism; 2) in vitro chromosomal instability evidence in human cells, other mammalian cells. Specific details regarding the studies within each of these lines of evidence were described in the preceding tables (Tables 4-35 to 4-37), and the body of evidence supporting the mode of action is summarized in Table 4-38. Evidence pertaining to tissue site specificity, dose-response concordance, and temporality is also summarized in Table 4-38. One limitation of the hypothesized mutagenic mode of carcinogenic action for dichloromethane is that the available data are generally limited to relatively high exposure studies. The authors speculated that these results are due to the instability of the reaction products (Hashmi et al. Bioactivation of a parent compound into a mutagenic metabolite resulting in cancer is a plausible mode of action of carcinogenicity in humans and is a generally accepted mode of action. Data are not available to support other possible modes of action for the liver and lung tumors in rodents. Efforts to observe sustained cell proliferation in liver following dichloromethane exposure of B6C3F1 mice have been unsuccessful. Groups of female B6C3F1 mice that were exposed to 0 or 2,000 ppm dichloromethane 6 hours/day, 5 days/week for up to 78 weeks did not exhibit enhanced cell proliferation in the liver when assessed at various intervals during exposure (Foley et al. Indices of enhanced cell proliferation have been measured in the lungs of male B6C3F1 mice following acute duration exposure at concentrations of about 1,500, 2,500, or 4,000 ppm dichloromethane (6 hours/day for 2 days) but not at exposure concentrations of 150 or 500 ppm 161 and not in lungs of Syrian golden hamsters exposed to concentrations up to 4,000 ppm (Casanova et al. The results suggest that enhanced cell proliferation is not sustained in the lung with longer-term exposure to dichloromethane concentrations associated with lung tumor development in mice, and that this mode of tumor promotion is not important in the development of dichloromethane-induced lung tumors. General Conclusions About the Mode of Action for Tumors in Rodents and Relevance to Humans Is the hypothesized mode of action sufficiently supported in test animals The mode of action for dichloromethane is hypothesized to involve mutagenicity via reactive metabolites. The extensive body of research examining the proposed mode of action was summarized in the previous section. The negative assays are generally those that were either micronucleus tests using mouse bone marrow, which is expected, as halogenated hydrocarbons (such as dichloromethane) are not very effective in this type of assay (Dearfield and Moore, 2005; Crebelli et al. Mutagenicity as a mode of action for carcinogenicity in humans is generally accepted and is a biologically plausible mechanism for tumor induction. The toxicokinetic and toxicodynamic processes that would enable reactive metabolites to produce mutations in animal models are biologically plausible in humans. The linearity of this metabolism at very low concentrations is discussed in the section on uncertainties in low-dose extrapolation (Section 5. According to the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (U. Although the database is lacking in vivo evidence of specific mutagenic events following chronic exposure to dichloromethane, the weight of the available evidence indicates that dichloromethane is acting through a mutagenic mode of carcinogenic action. Results from a developmental toxicity study in rats also raise concern for possible neurodevelopmental effects. Decreased offspring weight at birth and changed behavioral habituation of the offspring to novel 164 environments were seen following exposure of adult Long-Evans rats to 4,500 ppm for 14 days prior to mating and during gestation (or during gestation alone) (Bornschein et al. In the only other animal study examining possible early-life susceptibility to dichloromethane toxicity, Alexeeff and Kilgore (1983) found that exposure of young male mice to approximately 47,000 ppm for about 20 seconds significantly impaired the ability to learn using a passive-avoidance conditioning task. The broad issue of childhood susceptibility to chronic neurobehavioral effects of early life exposure represents a data gap in the understanding of the health effects of dichloromethane. This shift could affect cancer risk, given the evidence of genotoxicity through this metabolic pathway. However, the available data in humans are not sufficient to address the question of whether in utero or early life exposures represent a period of increased susceptibility to potential carcinogenic effects of dichloromethane. The estimates for categories based on concentration and frequency were similar, but there was no evidence for an increasing risk with increasing exposure level. Experiments comparing cancer responses from early-life exposures with those from adult exposures are not available for F344 rats or B6C3F1 mice, the strains of animals in which carcinogenic responses to dichloromethane have been observed. Groups of 60 male and 69 female newborns continued to be exposed after birth to 60 ppm dichloromethane 4 hours/day, 5 days/week for 7 weeks, followed by exposure 7 hours/day, 5 days/week for 97 weeks. Additional groups of 60 male and 70 female newborns were exposed after birth to 60 ppm dichloromethane 4 hours/day, 5 days/week for 7 weeks and then for 7 hours/day, 5 days/week for 8 weeks. For each animal sacrificed, histopathologic examinations were performed on the following organs: brain and cerebellum, zymbal glands, interscapular brown fat, salivary glands, tongue, thymus and mediastinal lymph nodes, lungs, liver, kidneys, adrenals, spleen, pancreas, esophagus, stomach, intestine, bladder, uterus, gonads, and any other organs with gross lesions.
Controls were frequency-matched by sex arthritis medical clinic etoricoxib 60 mg generic, age microcrystalline arthritis definition generic etoricoxib 60 mg otc, and vital status to the combined distribution of the cases arthritis finger joint cheap etoricoxib line. Methods and outcomes Exposure: Self-reported ever use of glyphosate herbicides collected through self-administered postal questionnaire and telephone interviews arthritis treatment vitamin d purchase cheapest etoricoxib and etoricoxib. Data analysis: Conditional logistic Potential controls were selected randomly regression. Cancer Outcomes for Solid Tumor-Types in Humans Exposed to Glyphosate-Containing Products Study author conclusions and limitations Conclusions: "No individual pesticides (including glyphosate) or broader category of pesticides, with or without proxy respondent, was associated with a statistically significant decrease or elevation in glioma risk. The accuracy and completeness of information given by proxy respondents varies by many factors. Another concern is the validity and reliability of the pesticide exposure assessment. Analyses were and 786 unexposed cases and separately conducted with or 147 exposed and 1,359 unexposed without proxy respondents. House and garden pesticide use: Glyphosate analysis included 51 exposed and 747 unexposed cases and 76 exposed and 1,099 unexposed controls. Analysis included 28 exposed and 410 unexposed cases and 75 exposed and 1,066 unexposed controls excluding proxy respondents. Randomly-selected, population-based controls were frequency-matched within a state. There was some evidence of an increased risk of acute myeloid leukemia for applicators, particularly in the highest category of glyphosate exposure compared with never users of glyphosate. Risk estimates were similar in magnitude between the unlagged and lagged (5 or 20 years) exposure analyses for all sites evaluated. Limitations: Some misclassification of exposure undoubtedly occurred; because the authors evaluated many cancer sites, there is the possibility that results were observed by chance and should therefore be interpreted with caution; the fact that no other studies have reported an association with acute myeloid leukemia also calls for cautious interpretation. However, 37% of the participants did not respond to follow-up, which may have resulted in an underestimation of Reference and study overview Andreotti et al. Lymphohematopoietic Cancer Outcomes in Humans Exposed to Glyphosate-Containing Products Study author conclusions and limitations glyphosate exposure though imputation procedures were used in an attempt to mitigate this issue. Limitations: Small number of specific cancers cases, only males included in the analysis, no information on timing of pesticide use. Set 1: 54,315 applicators, excluded those with cancer diagnosis before enrollment, those lost to follow-up, those who had missing data for age at enrollment, those who did not provide information on glyphosate use. Set 2: 49,211 applicators, additionally excluded those with missing data on education, smoking history, or alcohol used. Set 3: 40,719 applicators, additionally excluded those missing data on additional pesticide use. Outcomes: Incident cases identified between enrollment and December 31st from 2001 cancer registry files. Limitations: the small number of cases, absence of information on timing of pesticide exposure, unable to adjust for state of residence. Lymphohematopoietic Cancer Outcomes in Humans Exposed to Glyphosate-Containing Products Study author conclusions and limitations Reference and study overview those missing data for age at enrollment. Controls were a population-based, stratified sample of white men frequency-matched to the cases by 5-year age group, vital status at interview, and state of residence. Adjustments: Vital status, age, state, tobacco use, family history of lymphopoietic cancer, high-risk non-farming occupations, high risk exposures (benzene, naphtha, hair dyes). Conclusions: "Risks for all leukemia were not significantly increased among subjects who personally mixed, handled, or applied specific herbicides (including glyphosate). Potential inaccuracies in the evaluation of pesticide exposure could lead to exposure misclassification. Multiple statistical comparisons make it difficult to separate real association from chance findings. Lymphohematopoietic Cancer Outcomes in Humans Exposed to Glyphosate-Containing Products Study author conclusions and limitations Conclusions: Little evidence of an association between risk of multiple myeloma and exposure to pesticides (including glyphosate). Limitations: Small number of cases and controls, multiple statistical comparisons, and possibility of recall bias or chance. Glyphosate analysis included 11 exposed and 162 unexposed cases (n=173) for multiple myeloma and 40 exposed and 610 unexposed controls (n=650). Glyphosate analysis included four exposed B cell lymphoma cases and two exposed controls. Conclusions: No support to the role of occupation exposure to agrochemicals (including glyphosate) in etiology of B cell lymphoma. Glyphosate analysis included 36 exposed and 614 unexposed cases (n=650) and 61 exposed and 1,872 unexposed population based matched controls (n=1,933). Methods and outcomes Exposure: Interview self-reported never/ever glyphosate exposure. In Iowa, cases were ascertained from Iowa State Health Registry from 1981 to 1983 from males 30 years of age. In Minnesota, cases were ascertained from a surveillance system of Minnesota hospitals and pathology laboratories from 1980 to 1982 in males 30 years of age. In Kansas, cases were randomly selected from statewide cancer registry from males 21 years of age. Data analysis: Two models were used: (1) standard logistic regression and (2) hierarchical regression adjusted for age and study site. Limitations: No registries of pesticide use kept in Sweden, possible misclassification of pesticide exposure, no information gathered on protective equipment use. Methods and outcomes Exposure: Self-reporting questionnaires; never/ever glyphosate exposure. Data analysis: Conditional logistic regression analysis adjusted for both univariate and multivariate.
Other histologic lesions were minimal to mild arthritis medical treatment purchase etoricoxib with visa, placing renal failure as the likely cause of death arthritis in knee during pregnancy order etoricoxib line. Although it is not clear what role the kidney plays in disease arthritis pain relief options purchase etoricoxib 90 mg without a prescription, some believe that E arthritis neck glucosamine buy etoricoxib online from canada. Visceral gout was likely caused by the partial ureteral obstruction resulting from heavy diffuse lymphoplasmacytic infiltration in the wall of the ureter and (parasitized) epithelial wall hyperplasia. Spindle-shaped eggs, belonging to the blood fluke Dendritobilharzia anatinarum, were identified in kidney tissue pressed between glass slides in mallards (Anas platyrhynchos). The birds died from severe enteritis associated with blood fluke eggs, but no renal histology was described. They seldom cause problems and their eggs may be found in the feces and confused with other fluke eggs. Miscellaneous Parasites Other parasitic diseases also may be found incidentally in the kidneys of birds. Visceral larval migrans lesions consisting of a granulomatous reaction surrounding intact or degenerate Baylisascaris procyonis larvae in the renal (and other tissue) parenchyma of the house sparrow (Passer domesticus) were noted in one study. As most of the mixed species of birds had neural larval migrans only, the renal lesions seemed comparatively uncommon. While infected chickens developed no clinical signs and minimal evidence of infectivity, pigeons showed rapidly progressive disease (diarrhea, trembling, incoordination, death) and toxoplasma organisms in the kidney and other tissues. The authors stressed the importance of the pigeon crop in shedding the organisms with no emphasis on the kidneys. Avian macrophages have the capacity to convert vitamin D to its active form 1,25-dihydroxycholecalciferol. Hypercalcemia, hyperphosphatemia, hyperuricemia and elevated plasma creatine kinase were noted in the macaw. The cockatoo died 6 days after presentation and had chronic interstitial nephritis and calcifications in the kidney, proventriculus and lung. The macaw improved gradually and became disease free after discontinuing the supplemental vitamins and minerals. Hypercalcemia was attributed to oversupplementation with calcium and the vitamin mixture. It has been suggested that African grey parrots (Psittacus erithacus) may be susceptible to hypervitaminosis D,211 although no reviewed papers support this statement. Nephrosis Nephrosis is a non-specific histopathologic change characterized as any degenerative, non-inflammatory lesion of the kidney, from cloudy swelling to necrosis, whatever the cause. Due to its role in elimination, the avian kidney is vulnerable to the effects of many chemical toxins. Although many toxins have been shown to induce nephrosis and other kidney diseases, renal lesions caused by specific toxicities are difficult to prove outside of a controlled study. Hypercalcinosis High calcium intake also has been directly correlated with renal disease in birds. Clinically affected birds returned to normal and no new cases developed once the substrate was changed to acid-washed sand (0. However, there was a clear correlation with mild and severe metastatic (renal) mineralization in birds fed 0. This study suggests that some species, such as budgerigars, may be very sensitive to dietary calcium levels and that supplementation should be used cautiously. Hypovitaminosis A Hypovitaminosis A also may lead to renal disease in avian patients. In birds with hypovitaminosis A, the ureters and renal collecting ducts may undergo metaplasia, changing the normal double-layered epithelium to keratinized stratified squamous tissue. All affected birds observed by the author have been color variety cockatiels (Nymphicus hollandicus), lovebirds (Agapornis spp. With the exception of a history of predominately commercial pelletized diet, affected birds do not display any characteristics pathognomonic for "diet-induced renal disease. High-Cholesterol Diets Cholesterol supplemented in the feed can induce significant renal disease in pigeons. The kidneys of some affected birds are firm, diffusely off-white, have an irregular capsular surface and may be enlarged up to 3 times their normal size. All renal components are susceptible and lesions may include tubular degeneration and dilatation, glomerular hypercellularity and hypertrophy (proliferative glomerulopathy), periglomerular fibrosis, lipidladen cells within the glomeruli and multifocal, acute intersitial nephritis. However, this does bring up the potential complication of feeding some birds high-cholesterol foods. High-Protein Diets High-protein diets have been associated with renal disease in birds, but only under specific conditions. Compared to a low-protein diet group, pigeons fed a high-protein diet had an observed increase in drinking rates and urine production. A more detailed discussion of the effects of dietary protein and hyperuricemia are discussed under Part 2: Serum or Plasma-based Biochemistries, Uric Acid, and Part 2: Dietary Modification, Protein. Clinically affected birds had gross lesions that ranged from pale nephromegaly and hepatosplenomegaly to urolithiasis and visceral gout. Histologic lesions ranged from interstitial, perivascular and pericapsular nephritis to proliferative glomerulopathy, and severe tubular and glomerular atrophy and fibrosis in severe cases. The disease was termed "nephritis-nephrosis syndrome in poultry" and was eliminated when the ureaadulterated feed was replaced with a different balanced diet. Mycotoxic Nephropathy Mycotoxic nephropathy, due primarily to ochratoxin A, has been reported in chickens and ducks.
Observations and predictions of total expired dichloromethane resulting from gavage doses in ratsa Dichloromethane exhaled (% of dose) Observations Predictions Corn oil vehicle Water vehicle Global-fit Pankow-fit 36 rheumatoid arthritis edema cheap etoricoxib online amex. Assuming that this is supposed to be mg/kg baking soda arthritis relief discount 60 mg etoricoxib with visa, and assuming an average value of 250 g for a F344 rat arthritis knee early symptoms 60 mg etoricoxib with visa, an expiration of 1 rheumatoid arthritis commercial order etoricoxib 90mg without a prescription,300 mg/kg given a dose of 2,000 mg/kg corresponds to 65% of the administered dose. This value is consistent with their observation in mice where 55% was observed expired as dichloromethane from a dose of 500 mg/kg, with the percentage expired increasing with dose. A final comparison of model Variation C predictions to exhaled dichloromethane data is shown in Figure C-11. Model simulations for 1 and 50 mg/kg bolus oral doses are shown along with corresponding data from McKenna and Zempel (1981), as well as the data of Angelo et al. While the model matches the 50 mg/kg data of McKenna and Zempel (1981) quite well up to 1. The estimated fraction exhaled for a 1 mg/kg dose is likewise slightly below the observations for that exposure. However the discrepancies-less than 10% of the measured values-are well within what might result from experimental variability in both cases. Comparison of model Variation C predictions to dichloromethane exhalation data of McKenna and Zempel (1981) (data not used for model calibration) from bolus oral exposures to 1 and 50 mg/kg dichloromethane, along with 50 mg/kg bolus oral data of Angelo et al. Inclusion of lung metabolism in this model provides increased biological realism compared to the model of Andersen et al. It must also be noted that since the model assumes 100% absorption of an oral dose, there is no other route of elimination except systemic circulation. However, at lower doses or dose-rates, a larger fraction of the dose will be eliminated on firstpass through the liver, and hence never reach systemic circulation, which can give the appearance of lower bioavailability. Finally, when long-term exposure patterns (comparable to chronic bioassays) are simulated, the average rate of absorption must equal the average (measured or estimated) rate of ingestion, independent of the values for these constants. In comparing model predictions to a variety of data, one can say that while all of the model variations do a fairly good job of fitting some of the data, none of them fit C-29 all of the data very well, and there are some data for which none of the models provides a particularly good fit. With respect to the dichloromethane kinetics from inhalation and intravenous exposures shown in Figures C-3 to C-5, there was very little difference between predictions with the unadjusted parameters (Variation A) and the final revised parameters (Variation C). Therefore, Variation C is judged to be sufficiently better than the original model (Variation A) to support the use of Variation C instead of Variation A. Variation C was able to simulate exhaled dichloromethane data after oral dosing to which it had not been fit reasonably well (Figure C-11) and likewise provided fair agreement with watervehicle data from another source (Table C-4, Global-fit predictions at 250 and 500 mg/kg). Hence, the model is expected to adequately predict rat internal dosimetry (dichloromethane blood concentrations or rates of metabolism) under bioassay exposure conditions. Cellulose Triacetate Film Base Production Studies-Rochester, New York (Eastman Kodak) Friedlander et al. This study was expanded and extended several times during the next 20 years (Hearne and Pifer, 1999; Hearne et al. The first cohort (Cohort 1) consisted of 1,311 male workers employed in the roll coating division (n = 1,070) or the dope and distilling departments (n = 241) of the Eastman Kodak facility in Rochester, New York. Men who began working in these areas after 1945 and were employed in these areas for at least 1 year (including seasonal or part-time work that equaled 1 full-time year equivalent) from 1946 to 1970 were included. Follow-up time was calculated from the end of the first year of employment in the study area through December 31, 1994. The total number of person-years of follow-up was 46,112, and the mean duration of follow-up was 35. The second cohort (Cohort 2) included 1,013 male workers in the roll coating division who were employed for at least 1 year in this division between 1964 and 1970. Follow-up time was calculated from January 1, 1964, for those who were employed there before 1964, or the date of first employment in the roll coating division for those who began in 1964 or later. Total follow-up time was 26,251 person-years, and the mean duration of follow-up was 25. For both cohorts, cause of death was based on the underlying cause of death recorded on the death certificates, which were routinely obtained by the company for the processing of life insurance claims. The expected number of deaths was calculated using appropriate age-, sex-, calendar time-, and cause-specific death rates for men in New York State (excluding New York City). In addition, another referent group was also used in the analysis of the second cohort. This other referent was based on the age-, sex-, calendar time-, and cause-specific death rates of other hourly male workers employed at the Eastman Kodak plant in Rochester, New York. Cellulose triacetate was dissolved in dichloromethane and then cast into a thin film onto revolving wheels. The film was then cured by circulating hot air in the coating machines, and the solvent was recovered and redistilled. The exposure assessment in the Rochester, New York Eastman Kodak cohort studies was based on employment records (start and stop dates for specific jobs in the relevant areas of the company) in combination with air monitoring data used to estimate the exposure level for a given job, location, and time period (Hearne et al. In the most recent update (Hearne and Pifer, 1999), more than 1,500 area and 2,500 breathing zone air samples were used in the exposure assessment process. Reductions in exposures in the dope department and the distilling department began after 1965. There was little change in estimated exposures for jobs in the roll coating division from the 1940s through 1985, but some reduction was seen from 1986 to 1994.
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