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D R Mattison

Publications and source records attributed to D R Mattison.

At least 37 records · Page 2Linked to original sources
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Cyclosporine A: review of genotoxicity and potential for adverse human reproductive and developmental effects. Report of a Working Group on the genotoxicity of cyclosporine A, August 18, 1993.

Cyclosporine is an important therapeutic agent for transplant recipients and for a growing number of autoimmune diseases. Experimental animal and human data has indicated that cyclosporine is unlikely to be genotoxic. In contrast, azathioprine, an agent often given with cyclosporine, is considered to be genotoxic making the assessment of the independent effects of cyclosporine difficult. Cyclosporine does appear to be related to the development of tumors, primarily lymphomas, in animals and humans, but the basis of its potential carcinogenicity is not completely understood. In terms of reproductive and developmental toxicity, cyclosporine produces some adverse effects in both experimental animals and humans. In animals, the effects are seen at high doses sufficient to cause maternal toxicity. In humans, outcomes such as growth retardation have been noted, but the confounding effects of renal toxicity and resultant pregnancy complications cloud the interpretation. An increase in congenital anomalies and genetic disease have not been found reported in human studies that are limited in sample size. Given that the present data indicate the lack of genotoxicity, a mutation epidemiology study of cyclosporine is not recommended. As indicated above, such a study is probably impractical for many genetic endpoints of interest. However, well-conducted, large multicenter studies of transplant patients and their offspring would allow for routine monitoring of an increased risk for some reproductive and developmental (possibly non-genetic) endpoints that are of public health importance.

Animals↗
PubMed1994

Setting occupational health standards: toxicokinetic differences among and between men and women.

Differences between and among men, nonpregnant women, and pregnant women can influence exposure and response to workplace toxicants. These differences should be delineated, compared, and used when setting regulatory standards to protect workers from potentially hazardous workplace environments. Anatomical and physiological parameters include: body composition; surface area; blood, organ, and tissue volume; metabolism; and cardiovascular, pulmonary, gastrointestinal, and renal structure and function. Although men differ among themselves, on average, they also differ from women by weighing more, being taller, and having a larger surface area. Total body water is 40% greater in men than nonpregnant women; however, during pregnancy, body water increases from 29 to 33 liters. Extracellular and intracellular water volumes are smallest in nonpregnant women, increase with pregnancy, but remain smaller than those in men. Pulmonary function differs; pregnant women have the largest minute volume and greatest volume of air exchanged in an 8-hour period. This article compares anatomical, physiological, and toxicokinetic characteristics of men and nonpregnant and pregnant women to explore how differences in these factors contribute to variations in exposures, target tissue doses, and responses to workplace or environmental chemicals.

Absorption↗
PubMed1994

Intermediate variables as determinants of adverse pregnancy outcome in high-risk inner-city populations.

A probability sample survey of high-risk inner-city women with a live birth in the last 3 years shows that maternal medical risks and health behaviors during pregnancy are important intermediate variables influencing preterm delivery and birthweight. Women who developed two or more medical risks had about three-and-a-half times the risk of preterm delivery and two-and-a-half times the risk of low birthweight compared to those without such risks. Women with prior fetal loss had twofold increase in the risk of preterm delivery and low birthweight. Unintended pregnancy resulted in one-and-a-half to twofold increase in preterm delivery and low birthweight, respectively. Inadequate gestational weight increased the risk of preterm delivery by about 50%. Smoking during pregnancy raised the risk of low birthweight slightly more than one-and-a-half times.

Adolescent↗
PubMed1993

Sites of female reproductive vulnerability: implications for testing and risk assessment.

All reproductive toxicity testing, whether in vivo or in vitro, should be conducted with consideration of the ultimate use of the data for reproductive risk assessment and the protection of human reproductive health. In this review selected sites of vulnerability in the female reproductive system are identified. These sites of female reproductive vulnerability may be utilized for in vitro toxicity testing assays, and the data from assays may be employed in the hazard identification and hazard characterization steps necessary for reproductive risk assessment. Using biomarkers of female reproductive function derived from in vitro toxicity testing it is possible to define functions that characterize female fecundity. These characterizations of female fecundity may be used to quantitate reproductive risk in human populations.

Animals↗
PubMed1992

The effect of benzo(a)pyrene on murine ovarian and corpora lutea volumes.

OBJECTIVE: Women who smoke have impaired fertility and experience menopause at an earlier age. This experiment determined the effect of benzo(a)pyrene, a polycyclic aromatic hydrocarbon contained in cigarette smoke, on murine ovarian volume, total corpora lutea volume, individual corpora lutea volumes, and corpora lutea numbers. STUDY DESIGN: C57BL/6N mice were treated with intraperitoneal injections of 0 to 500 mg/kg benzo(a)pyrene in corn oil. The 20 mice at each dose were divided into four groups of five each and were killed at 1, 2, 3, or 4 weeks after treatment. Ovaries were serially sectioned and analyzed morphometrically. RESULTS: Benzo(a)pyrene produced a dose- and time-dependent decrease in ovarian volume, total corpora lutea volume, and number of corpora lutea per ovary. This effect was transitory at low doses with complete recovery of corpora lutea by 4 weeks. Compensatory hypertrophy of the individual corpora lutea occurred during the recovery phase. Ovarian function did not return in animals treated with the two highest doses. CONCLUSION: Benzo(a)pyrene is a murine ovarian toxicant that inhibits corpus luteum formation in a dose- and time-dependent fashion.

Animals↗
PubMed1992

Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 1. Effects on ovarian structure and function.

The antineoplastic alkylating agent, cyclophosphamide (CPA) is known to impair normal female reproductive function. We have examined the time- and dose-dependent effects of CPA on the ovary, specifically, its impact on follicle numbers, ovarian morphometrics, and estradiol (E2) production. Female C57BL/6N mice were treated ip with CPA in normal saline at doses of 0, 75, 200, or 500 mg/kg. Ovaries were removed 1 to 14 days following treatment and serial sections were prepared. Differential follicle counts revealed that primordial follicles were most sensitive to CPA (ED50 = 122 mg/kg), followed by antral and growing follicles. Primordial follicles were affected by all doses of CPA and were completely destroyed by 3 days in the 500 mg/kg dose group. The greatest reduction in antral follicles was to 49% and 7% of controls by CPA doses of 200 and 500 mg/kg, respectively. Plasma E2 concentrations correlated best with antral follicle numbers (r2 = 0.94) and antral follicle volume (r2 = 0.88). Growing follicles were least sensitive to CPA and only decreased at 7 and 14 days. Although atretic changes were observed in growing follicles after treatment with CPA, these follicles recovered and progressed into apparently functional antral follicles (that is, they produced E2). Total ovarian volume was significantly reduced (30 to 40%) in the high-dose group on day 1, and remained depressed throughout the experiment. Examination of ovarian morphometrics indicated that this volume loss represented specific temporal changes in corpora lutea (CL), interstitial tissue, growing follicles, and antral follicles. At 1 and 3 days after treatment, the major loss in ovarian volume was due to a reduction in antral follicle and interstitial tissue volumes, while at 7 days the majority of volume loss was accounted for by the absence of CL. It is not known if CL are directly affected by CPA at the early time points, but their absence at 7 and 14 days is probably due to earlier destruction of antral follicles. These results demonstrate that CPA-induced ovarian toxicity is exhibited as temporal changes in both structural and functional features of the ovary, particularly in destruction of primordial and antral follicles and depressed E2 production. Information of this type also gives insight into ovarian response to chemical disruption of folliculogenesis and its recovery process.

Animals↗
PubMed1992

Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 2. Effects on uterine structure and function.

Cyclophosphamide-induced uterine weight loss was evaluated to determine whether it was a function of primary toxicity to the uterus or a secondary response to ovarian toxicity, that is, antral follicle destruction. C57BL/6N mice treated with cyclophosphamide exhibited a reduction in uterine weight concurrent with a decrease in plasma estradiol (E2) concentrations, thereby indicating toxicity to the ovary. However, when E2 concentrations recovered, uterine weight still remained depressed, suggesting that cyclophosphamide also impaired uterine function. Further investigation revealed that cyclophosphamide altered the normal uterotropic response to E2, significantly diminishing the uterine weight gain associated with E2 treatment. We conclude that effects of cyclophosphamide on the uterus involve two components: 1) decreased uterine weight in response to decreased plasma E2 resulting from ovarian toxicity, and 2) an altered response to E2 due to direct uterine toxicity.

Animals↗
PubMed1992

Morphometric assessment of the murine ovarian toxicity of 7,12-dimethylbenz(a)anthracene.

7,12-Dimethylbenz(a)anthracene (DMBA) is a polycyclic aromatic hydrocarbon and a component of cigarette smoke that has been identified as a murine reproductive toxicant. The morphometric parameters of total ovarian volume, individual corpus luteum volumes, and total corpora lutea volume were measured in C57BL/6N mice treated with DMBA. Each group received single intraperitoneal injections of 0, 0.1, 1.0, or 10 mg/kg and were sacrificed at 1, 2, 3, or 4 weeks after treatment. DMBA produced a dose-dependent decrease in ovarian volume and number of corpora lutea in each ovary. The observed reduction in total corpora lutea volume did not fully account for the loss in total ovarian volume. This is consistent with previous descriptions of a toxic effect on all ovarian components including growing and resting follicles. Growing follicles that escaped the toxic effects of DMBA and achieved ovulation resulted in a corpus luteum that appeared histologically normal. Morphometric analysis of this animal model further defines the dynamic changes in the mouse ovary in response to DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

MR imaging in high-risk obstetric patients: a valuable complement to US.

The accuracy of prenatal diagnosis has become increasingly critical in the field of high-risk obstetrics. Although ultrasound (US) provides adequate information in most cases and continues to be the initial prenatal examination of choice, there are instances in which the results of the US study may be equivocal. The role of magnetic resonance (MR) imaging was explored in 27 selected patients with various indications to determine its effectiveness as a complement to US. MR imaging was most helpful in the diagnosis of extrauterine gestation, evaluation of placental position, determination of extent or nature of masses associated with pregnancy, and differentiation between diaphragmatic hernia and a thoracic mass. Although MR imaging did not add information that affected the accuracy of the diagnosis of oligohydramnios, in all other cases it provided an extra dimension in diagnosis by showing clearer anatomic relationships in the pelvis. It has proved to be a valuable complement to an equivocal US study.

Diagnosis, Differential↗
PubMed1992

Pesticide concentrations in Arkansas breast milk.

During an episode of pesticide dairy product contamination in Arkansas in 1986, breast milk samples from 942 women were analyzed for concentrations of chlorinated pesticides. The pesticides found most frequently in quantifiable concentrations were p,p'-DDE (100%), oxychlordane (84%), trans-nonachlor (77%), heptachlor epoxide (74%) and beta-HCH, an isomer of lindane (27%). The pesticides present in highest mean concentrations of all samples analyzed (reported as ppm in milk fat) were p,p'-DDE (0.952 ppm), trans-nonachlor (0.062 ppm), oxychlordane (0.051 ppm), heptachlor epoxide (0.045 ppm), p,p'-DDT (0.039 ppm), and beta-HCH (0.032 ppm). These concentrations are lower than previous reports from similar regions of the US. However, continued persistence in human breast milk is of concern due to potential adverse health effects from these chemicals.

Adolescent↗
PubMed1991

Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide.

Although cyclophosphamide (CPA) is an ovarian toxicant, the responsible metabolite(s) have not been identified. The purpose of these experiments was to determine if phosphoramide mustard or acrolein were the proximate toxicants produced by metabolic activation of CPA. To do this analogs of CPA known to generate either phosphoramide mustard or acrolein in vivo were assessed for their ability to produce ovarian toxicity as measured by differential follicle destruction, ovarian volume loss, and uterine weight loss and compared to the effects produced by CPA. Phosphoramide mustard cyclohexylamine salt (PMC) and trans-4-phenylcyclophosphamide (T4P), both of which generate phosphoramide mustard, and didechlorocyclophosphamide (DCPA) and allyl alcohol (AA) which generate acrolein were administered ip to female C57BL/6N mice, 10-12 weeks old, at doses equimolar to 0, 25, 75, 200, or 500 mg/kg of CPA. Three days later the animals were killed, their uterine weights measured and their ovaries removed, fixed, and serially sectioned. Only PMC and T4P produced ovarian toxicity. On an equimolar basis these compounds were over twice as potent as CPA. Both caused a significant reduction in uterine weight (to 50% of controls) at doses of 200 (PMC) and 150 mg/kg (T4P). PMC and T4P also caused a 50% reduction in ovarian volume at doses above 75 mg/kg. Primordial follicles were most sensitive; ED50s were 76.9, 25.3, and 19.3 mg/kg (0.276, 0.091, and 0.069 mmol/kg) for CPA, PMC, and T4P, respectively. Growing follicle numbers were also reduced by T4P and PMC, an effect not seen with CPA treatment. Finally, antral follicles were significantly reduced by all doses of PMC, and with T4P at doses greater than 75 mg/kg. The highest doses of PMC, T4P, and CPA all caused a reduction in antral follicle numbers to less than one percent of controls. Didechlorocyclophosphamide (DCPA) and allyl alcohol (AA), compounds that generate acrolein but not phosphoramide mustard in vivo, had no effect on any of the parameters measured even when injected directly into the ovary. This suggests that phosphoramide mustard is responsible for CPA ovarian toxicity. The greater potency of PMC and T4P compared to CPA is likely the result of these compounds bypassing important detoxification steps, therefore, more of the parent compound reaches the ovary as the toxic metabolite.

1-Propanol↗
PubMed1991

Physiological alterations during pregnancy: impact on toxicokinetics.

The physiological changes that occur in the alimentary, cardiovascular, pulmonary, and renal organ systems during pregnancy are designed to increase availability of nutrients to and remove wastes from the fetus. Although this is a general requirement, not all animals use the same strategies to meet these goals. These physiological adaptations will impact on toxicokinetics and may alter toxicodynamics. Absorption, distribution, metabolism, transfer between maternal and fetal compartments, and elimination will change for many xenobiotics during pregnancy. The changes in body weight, total body water, plasma proteins, body fat, and cardiac output will alter the distribution of many xenobiotics (Hytten and Leitch, 1971; Hytten and Chamberlain, 1980; Mattison, 1986). As the toxicokinetic parameters change across species, it is important to understand their impact on chemicals associated with maternal, placental, and fetal toxicity for appropriate cross-species extrapolation.

Adaptation, Physiological↗
PubMed1991

Comparison of random and serial sections in assessment of ovarian toxicity.

Assessment of ovarian toxicity by follicle quantitation and morphometric analysis of serial sections is time consuming and expensive. This report compares the estimation of follicle number obtained from counting oocytes in serial sections or 5 random sections of mouse ovaries. Ovaries were obtained from C57BL/6N and B6C3F1 mice treated with ovarian toxicants. C57BL/6N mice were treated with cyclophosphamide (0, 75, 200, and 500 mg/kg, ip) and killed at 24, 72, and 168 h. B6C3F1 mice were treated daily, ip, with 4-vinylcyclohexene (0, 100, 400, and 800 mg/kg/day for 30 days), vinylcyclohexene diepoxide (0, 10, 40, and 80 mg/kg/day for 30 days), or benzo(a)pyrene (100 mg/kg, single dose) and killed on day 31. Ovarian serial sections were prepared and oocytes counted in every tenth section. When serial sections were evaluated, 30 to 60 sections were counted. Random section counting involved randomly selecting 5 sections from the 30 to 60 sections previously counted by the serial method. Chemically-induced follicle loss was evident by the reduction in follicle counts relative to control animals when estimating follicle number using serial or random section counting. Furthermore, a linear regression analysis of follicle counts over all treatment groups showed that the highest correlation between random and serial section counting and was for primordial follicles. Correlation coefficients (R2) for each follicle type were: primordial--C57BL/6N 0.82, B6C3F1 0.86; growing--C57BL/6N 0.16, B6C3F1 0.46; antral--C57BL/6N 0.07, B6C3F1 0.11. Although other screens may need to be developed for growing and antral follicles, primordial follicle toxicity is adequately defined by counting 5 random sections.

Animals↗
PubMed1991

Oxytocin pharmacodynamics: effect of long infusions on uterine activity.

Despite common use in obstetrics for almost 50 years, there is still disagreement concerning optimal clinical protocols for the use of oxytocin. This disagreement arises in part from inadequate data on oxytocin pharmacokinetics and pharmacodynamics. This report evaluates the uterine response to fixed doses of oxytocin (1-3 mIU/min) over long infusion times (up to 120 min) in 10 patients with secondary arrest of dilatation. The uterine activity increased from 132 +/- 61 Alexandria units during the control period to 199 +/- 64 Alexandria units at an infusion rate of 1 mIU/min. Increasing the infusion rate to 2 mIU/min increased the uterine activity to 240 +/- 64 Alexandria units. The uterine activity increased until a steady state was achieved between 40 and 70 min after the initiation of infusion. Continuing the infusion at a fixed rate for more than 90 min appears to result in a decreasing uterine activity. Patients requiring oxytocin for augmentation of labor developed adequate uterine activity with dose rates of 1-3 mIU/min. Clinical protocols for oxytocin augmentation with an interval of 40-60 min between increases in the dosing seem reasonable based on these pharmacodynamic data.

Dose-Response Relationship, Drug↗
PubMed1991

An overview on biological markers in reproductive and developmental toxicology: concepts, definitions and use in risk assessment.

Reproduction and development are complex couple-dependent processes. Risk assessment for these health outcomes requires the use of biomarkers to link exposures to disease. Biological markers of susceptibility, external dose, internal dose, biologically effective dose, early or late biological responses, altered reproductive or developmental function, and reproductive or developmental disease are introduced. Using these biomarkers it is possible to define a biologically based risk assessment methodology for reproductive and developmental toxicity. Risk assessment for reproductive toxicity requires definition of male and female fecundity, couple-specific factors, spontaneous abortion rate, and other factors. Using using sperm count as a biomarker for male fecundity, an example of a reproductive risk assessment using biomarkers is performed.

Biomarkers↗