Overview: new perspectives on the stubborn challenge of preterm birth.
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Congresses as Topic↗
Biomedical subjects
D R Mattison
Publications and source records attributed to D R Mattison.
Preterm delivery: a public health perspective.
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Female↗
The unnecessary epidemic of folic acid-preventable spina bifida and anencephaly.
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Anencephaly↗
Structural determinants of developmental toxicity in hamsters.
A CASE/MULTICASE structure activity relationship (SAR) model of developmental toxicity of chemicals in hamsters (HaDT) was developed. The model exhibited a predictive performance of 74%. The model's overall predictivity and informational content were similar to those of an SAR model of mutagenicity in Salmonella. However, unlike the Salmonella mutagenicity model, the HaDT model did not identify overtly chemically reactive moieties as associated with activity. Moreover, examination of the number and nature of significant structural determinants suggested that developmental toxicity in hamsters was not the result of a unique mechanism or attack on a specific molecular target. The analysis also indicated that the availability of experimental data on additional chemicals would improve the performance of the SAR model.
Algorithms↗
Modeling adverse environmental impacts on the reproductive system.
When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method.
Animals↗
Ethics instruction at schools of public health in the United States. Association of Schools of Public Health Education Committee.
OBJECTIVES: A survey of US schools of public health was undertaken in 1996 and 1997 to obtain a general picture of public health ethics curricula. METHODS: An explanatory letter with a list of questions for discussion was sent to the deans of the accredited US schools of public health. The deans were asked that at least 1 individual at their school who "is most knowledgeable about ethics curricula" review the list of questions and complete an ethics survey contact form. RESULTS: Ethics instruction was required for all students at only 1 (4%) of the 24 schools surveyed, while 7 schools required ethics instruction for some students. Two of the schools had no ethics courses. Ethics instruction was required for all MPH students at 9 (38%) of the schools and for all doctoral students at 4 (17%) of the schools. Most of the schools (19 of 24, or 79%) offered short courses, seminar series, or invited lectures on ethical topics, and 23 (96%) included lectures on ethics topics in other courses such as health law. CONCLUSIONS: Training programs at US schools of public health vary greatly in how much attention is given to ethics instruction. Model curricula in public health ethics should be developed to help fill this gap.
Curriculum↗
Folic acid requirements for women of childbearing age.
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Adolescent↗
Human developmental toxicity and mutagenesis.
A previously described SAR model of human developmental toxicity was analyzed further. The model shows a number of mechanistic similarities with SAR models of other toxicological phenomena (systemic toxicity, chromosomal and genomic effects). This implies that there are many targets associated with developmental effects. Surprisingly the analyses revealed no significant mechanistic overlap between developmental toxicity in humans and mutagenicity in Salmonella, a surrogate for the occurrence of point mutations. Our study indicates that this lack of similarity is likely the result of the pre-screening strategies which largely eliminate Salmonella mutagens from among the therapeutics introduced into human medicine.
Animals↗
Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays.
Ovaries from National Toxicology Program Reproductive Assessment by Continuous Breeding (RACB) bioassays were used to directly compare differential ovarian follicle counts and reproductive performance for 15 chemicals. Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 microm. Counts of small, growing, and antral follicles were obtained in every 10th section. For all follicle types, younger mice had more follicles than older mice, and CD-1 mice had more follicles than age-matched animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive outcome in one or both sexes of mice, with six agents affecting females (R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777). Three of six female toxicants [2,2-bis(bromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] significantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strains. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle numbers were proportional to dose. In CD-1 mice, female toxicants di-N-hexyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not affected by toxicants for which the susceptible sex could not be determined (bisphenol A, ethylene glycol, oxalic acid). Altered follicle counts without apparent reproductive impairment occurred in CD-1 mice at lower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproductive toxicity than fertility.
Age Factors↗
Structural determinants associated with risk of human developmental toxicity.
OBJECTIVES: Identifying drugs or chemicals that represent hazards to human development is a continuous challenge. Of the approximately 60,000 chemicals in commercial use only 5% have been evaluated for developmental toxicity. Identification of inexpensive, rapid, validated techniques to demonstrate chemical hazards for the human embryo or fetus is the objective of this research. STUDY DESIGN: This research explored identification of structure activity predictors associated with human developmental toxicity by means of MULTICASE (multiple computer-automated structure evaluation), an algorithm that evaluates associations between chemicals and their constituent fragments and a biologic response. This algorithm allows identification of chemicals (and specific substructures) that may be human developmental toxicants. Developmental toxicity data were compiled from two sources (the Teratogen Information System and Food and Drug Administration guidelines) and analyzed to identify structural determinants (biophores) associated with human developmental toxicity. RESULTS: This analysis identified 17 biophores associated with human developmental toxicity. Testing the biophores against the learning set demonstrated 99% concordance, 100% sensitivity, and 98% specificity. Cross-validation studies were conducted, in which the original database was randomly separated into five learning and test sets; these demonstrated a mean concordance of 73%, with a mean sensitivity of 63% and a mean specificity of 79%. CONCLUSIONS: The MULTICASE structure-activity model is useful for identifying potential human developmental toxicants, as well as serving as a starting point for mechanistic investigations.
Algorithms↗
Energy charge monitoring via magnetic resonance spectroscopy 31P in the perfused human placenta: effects of cadmium, dinitrophenol and iodoacetate.
Phosphorus 31 nuclear magnetic resonance spectroscopy as a non-invasive technique was applied to monitor the metabolic activity of the human placenta during perfusion in vitro. During control perfusions (n = 3) there was an initial increase in adenosine triphosphate (ATP) and a fall in inorganic phosphate (Pi). Thereafter, however, the level of both ATP and Pi remained constant throughout the perfusion period (11 h). Additional biochemical parameters such as glucose consumption, lactate production and the release of hormones, human chorionic gonadotrophin (hGC). measured in the perfusate samples, were also used to assess the viability of the placental tissue. As with ATP, all these biochemical parameters under the control conditions showed a stable rate of metabolic activity throughout the length of the experiments. In additional experiments, the effect of the metabolic inhibitor dinitrophenol (n = 2) and dinitrophenol (DNP) together with iodoacetic acid (IOA, n = 2) were studied. DNP (0.1 mM) alone showed a slight decrease of all parameters. In contrast, the addition of IOA (0.1 mM) with DNP (0.1 mM) not only blocked the production of ATP but also produced a substantial impact on placental metabolic activity. The effect of a toxic dose of cadmium (20 nmol/ml) was studied also (n = 3). This dose of cadmium demonstrated no effect on phosphorus metabolism. However, the rate of glucose consumption and the release of hCG were significantly reduced.
Adenosine Triphosphate↗
Impact of cocaine on human placental function using an in vitro perfusion system.
The transport of cocaine from the maternal to fetal circulation and the effect of cocaine on placental function was investigated in vitro using dually perfused term human placentae with recirculation of both maternal and fetal perfusates. In the first experimental group (n = 5, 2 hr), after addition of 3H-cocaine and 14C-inulin to the maternal circulation, steady state concentrations were achieved within 20 min on the maternal side. However, in the following 100 min, uptake of 3H-cocaine remained higher than of the 14C-inulin on the maternal side. 3H-Cocaine was transported more rapidly than 14C-inulin into the fetal circulation and was detected within 10-15 min of initiation of perfusion. In the second experimental group (n = 6), the maternofetal permeability of 14C-insulin was determined in the same placental perfusion in both the absence (control period, 2 hr) and presence of cocaine (test phase, 2 hr) with its 3H-tracer. After the addition of cocaine (2-3 mg/L), the transfer of 14C-inulin was reduced from 6.59 to 3.64 mL/gm per min (p < .001), indicating that cocaine alters placental permeability. In addition to its effect on placental permeability, cocaine decreases the rate of release of hCG into the maternal circulation--reduced from 3.11 (control period) to 1.62 IU/min (test phase, p < .01).
Cocaine↗
Continuous measurement of ATP by 31P-NMR in term human dually perfused placenta in vitro: response to ischemia.
ATP was examined in dually perfused term human placentas by using 31P-nuclear magnetic resonance (NMR) spectroscopy. 31P-NMR spectra were acquired every 30 min starting approximately 30 min after establishing fetal and maternal perfusions, and maternal perfusate samples were obtained to monitor glucose utilization, lactate production, and human chorionic gonadotropin (hCG) and human placental lactogen (hPL) release. In continuous-perfusion experiments, placentas were perfused as long as 10 h. ATP increased and Pi fell after initiation of perfusion. Fetal volume loss was < 2 ml/h, and constant production of hCG, hPL, and lactate as well as constant utilization of glucose were observed. In additional experiments, ischemia was produced by halting maternal and fetal perfusion pumps after a 2-h control period. After 2, 3, or 4 h of ischemia, ATP decreased 46 +/- 17, 51 +/- 5, and 85% of control, respectively. When perfusion was reinitiated, ATP increased and was maintained for the duration of the experiment (an additional 2 h). Recovery of ATP after reperfusion was not paralleled by recovery in glucose utilization, lactate production, or hPL and hCG release. However, during the reperfusion period, fetal pressure was < 70 mmHg and fetal volume loss was < 2 ml/h. These investigations suggest that the dually perfused human placental lobule can maintain ATP for > or = 10 h. Although the perfused human placenta recovers ATP and maintains fetal perfusion volume after ischemia lasting up to 4 h, utilization of glucose, production of lactate, and production and release of hCG and hPL are impaired.
Adenosine Triphosphate↗
Continuous pO2 monitoring during dual perfusion of the term human placenta in vitro.
A computerized system has been developed to continuously monitor, collect and display pO2 in real time from the maternal and fetal arteries and veins in the dually perfused term placenta. Oxygen electrodes were installed in flow-through chambers in the tubing of the perfusion system. The signal from the O2 electrodes was digitized, acquired, analyzed and displayed in real time during the perfusions using a personal computer. Output from the O2 electrodes was linearly proportional to pO2 (33-502 mm Hg; r2 = 0.99). Running average pO2 values (mean +/- SD) were also calculated for every minute and stored. The captured data files can be recalled and analyzed after completion of the perfusion experiment and compared with other data collected during perfusion. One of the unique capabilities of the pO2 electrodes is their ability to respond rapidly to changing perfusion conditions. For example, as the fetal circulation begins to break down the change is noted before volume loss in the fetal circuit by decreasing fetal vein pO2.
Biological Transport↗
Summary of the workshop on issues in risk assessment: quantitative methods for developmental toxicology.
This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.
Animals↗
Structural determinants of developmental toxicity.
Developmental toxicity, an area of public concern, suffers from the lack of accessible, reliable, peer-reviewed compilations of data and substantial gaps in testing. These deficits frequently make it necessary for regulatory agencies to use other toxicological end points to regulate developmental toxicants. We have utilized a database of chemicals identified as developmental toxicants in rats, mice, rabbits, and humans and an expert system which learns the association between molecular structure and biological response (Computer Automated Structure Evaluation; CASE) to explore structure-activity relationships in developmental toxicity. Developmental toxicity was defined as death, growth retardation, or structural or functional malformations. In analyzing the data CASE selects its own molecular descriptors from a learning set of active and inactive molecules. Using randomly constructed learner and tester sets, the concordance of the predictions with the actual data was between 77 and 82%. CASE identified 13 major structural fragments associated with developmental toxicity in mice, 15 in rats, 9 in rabbits, and 7 in humans. These analyses indicate that there is indeed a structural basis for developmental toxicity which may be used to predict the developmental hazard of untested or inadequately tested chemicals.
Animals↗
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↗