PubMed Health⌕ Search

Biomedical subjects

P W Peters

Publications and source records attributed to P W Peters.

At least 19 recordsLinked to original sources
PubMed1998

Developmental toxicology: adequacy of current methods.

Toxicology embraces several disciplines such as carcinogenicity, mutagenicity and reproductive toxicity. Reproductive toxicology is concerned with possible effects of substances on the reproductive process, i.e. on sexual organs and their functions, endocrine regulation, fertilization, transport of the fertilized ovum, implantation, and embryonic, fetal and postnatal development, until the end-differentiation of the organs is achieved. Reproductive toxicology is divided into areas related to male and female fertility, and developmental toxicology. Developmental toxicology can be further broken down into prenatal and postnatal toxicology. Today, much new information is available about the origins of developmental disorders resulting from chemical exposure. While these findings seem to promise important new developments in methodology and research, there is a danger of losing sight of the precepts and principles established in the light of existing knowledge. There is also a danger that we may fail to correct shortcomings in our existing procedures and practice. The aim of this presentation is to emphasize the importance of testing substances for their impact in advance of their use and to underline that we must use the best existing tools for carrying out risk assessments. Moreover, it needs to be stressed that there are many substances that are never assessed with respect to reproductive and developmental toxicity. Similarly, our programmes for post-marketing surveillance with respect to developmental toxicology are grossly inadequate. Our ability to identify risks to normal development and reproduction would be much improved, first if a number of straightforward precepts were always followed and second, if we had a clearer understanding of what we mean by risk and acceptable levels of risk in the context of development. Other aims of this paper are: to stress the complexity of the different stages of normal prenatal development; to note the principles that are applicable in developmental and especially prenatal toxicology; to describe the different agents that might act as developmental toxicants or teratogens; to show the broad scope of different effects caused by developmental toxic agents; and to indicate methods to detect and to recognise causes of developmental defects with the primary objective of preventing these disorders.

Abnormalities, Drug-Induced↗
PubMed1997

Heterogeneity of spina bifida.

Splitting birth defects into dysmorphologically homogeneous groups might improve the ability to detect a genetic risk factor or teratogenic exposure. With regard to spina bifida, recent studies suggest that etiologic heterogeneity exists within the group of spina bifida, although exogenous risk factors have been sparsely evaluated for subgroups. In the present study, 210 spina bifida patients were classified into relatively homogeneous groups, based on retrospective information on appearance and functional aspects of the lesion abstracted from medical records of the patients. We compared high with low spina bifida, and open with closed spina bifida, and investigated whether risk factors for spina bifida such as maternal age, antiepileptic drug use, parental occupation, and genetic factors were specifically associated with these homogeneous subclasses. For these comparisons, a referent group of 671 children was used. Although classifying spina bifida into homogeneous subclasses presented some difficulties and numbers were small, this study provides some evidence for different risk profiles for subclasses of spina bifida. The sex ratio, the proportion of miscarriages of siblings, and maternal age did not differ among the different subclasses of spina bifida. However, children with a positive family history of neural tube defects (NTDs) had a higher risk of high spina bifida [odds ratio (OR) = 6.3, 95% confidence interval (CI): 1.7-19.2] than of low spina bifida (OR = 2.1, 95% CI: 1.0-4.2). Siblings with NTDs were more common in cases with high spina bifida and cases with open spina bifida. A strongly increased risk of high spina bifida was found for male welders (OR = 12.1, 95% CI: 1.5-64.2), whereas the risk of low spina bifida was much lower (OR = 1.6, 95% CI: 0.2-7.9). For mothers with agricultural occupations, a strongly increased risk was observed for open spina bifida (OR = 14.3, 95% CI: 2.9-77.7), whereas none of 107 cases with closed spina bifida had a mother with an occupation in agriculture. Due to small numbers, the results must be interpreted with caution.

Adult↗
PubMed1993

Effects of cadmium on reproduction, an epizootologic study.

The Dutch part of Kempenland has been exposed to cadmium pollution since the last century. Experimental data suggest effects by cadmium on reproduction such as diminished fertility, decreased foetal growth, and specific malformations. Use was made of a historical cohort of dairy cows, ascertained from a surveillance program conducted by the regional Veterinary Health Service between 1976 and 1986. Ten dairy farms in the cadmium region were matched by size with 40 dairy farms from a reference area. Logistic models were used to calculate Odds (OR) and Rate Ratios (RR) and their 95% confidence interval. In total 4,039 exposed and 15,552 reference gestations were compared. The reasons for the slaughter of 574 exposed and of 2,824 reference cows were ascertained. A lower twinning rate [OR = 0.63 (0.47-0.84)] was found and more birth complications, for both calves [OR = 1.50 (1.25-1.80)] and cows [OR = 1.49 (1.24-1.79)]. More inseminations [OR = 1.20 (1.01-1.43)] were needed for conception in the exposed area. Deaths among twins [OR = 1.66 (0.90-3.07)] were not significantly higher. Perinatal death, premature death, age at, or reasons for, slaughter were not consistently different. These results are consistent with those of other observational and experimental studies. Extrapolation from these large domestic animals to humans is problematic, as is the more frequent extrapolation from rodents to humans. It can be concluded that longterm exposure to low levels of cadmium is associated with impaired reproduction in dairy cows.

Animals↗
PubMed1993

Risk assessment of drug use in pregnancy: prevention of birth defects.

Some developmental disorders are preventable by primary prevention, i.e. by avoiding exposure to microorganisms or chemicals that cause developmental disorders. This is not only important for physicians prescribing drugs, midwives monitoring pregnancies, but especially for parents taking the responsibility of having a baby; moreover, this fact is of importance for teratogen information services and public health authorities, both having preventive roles to play. Knowledge of the different pre- and postnatal developmental stages and the reproductive cycle is essential to understand this statement. The basic principle in reproductive toxicology and teratology is that the response of an organism to a teratogen depends upon the nature and the dosage of the substance, the stage of development of the embryo/fetus and its genetic make up. Chemical agents of different nature can induce developmental disorders either via the mother and perhaps via the father. The common consent that the vulnerable stage of development is only the first trimester of pregnancy is not correct. From oogenesis and spermatogenesis to at least the first years of life the developing organism is susceptible to harmful effects of chemical agents, including drugs. Developmental disorders include not only malformations visible at birth, but also spontaneous abortions, fetal death and functional deficits including behavioural defects. Studies both in the human and in laboratory animals make it possible to select substances to avoid exposure to developmental toxicants which are already on the market or still under development. This implicates a multi-step procedure leading from risk-evaluation, risk-assessment, and risk-communication to risk-perception and the according action (risk-management).

Abnormalities, Drug-Induced↗
PubMed1992

Intrauterine diethyltoluamide exposure and fetal outcome.

The CNS toxicity of the insect repellent, diethyltoluamide (DEET), has been documented by several publications on severely affected adults and children. We report a 4-year-old boy with mental retardation, impaired sensorimotor coordination, and craniofacial dysmorphology, whose mother applied DEET daily throughout her whole pregnancy in addition to the prophylactic use of chloroquine.

Abnormalities, Drug-Induced↗
PubMed1991

Interlaboratory evaluation of three culture media for postimplantation rodent embryos.

The first aim of the study was to compare the ability of rat serum, human serum, and a mixture of human and rat serum (4:1) to support in vitro development of rodent postimplantation embryos. The comparison was made in three laboratories using rat embryos and in one laboratory using mouse embryos. Batches of sera, initial developmental stage, duration of culture, and endpoints were identical in the laboratories. The second aim of the study was to evaluate if other variables that could not be standardized would significantly influence the results of the laboratories. No reproducible difference was observed among the culture media or among the laboratories except that growth and differentiation were slower in the laboratory using mouse embryos. Further experiments are needed to exclude small differences in performance of the media.

Animals↗
PubMed1991

Biotransformation of cyclophosphamide in post-implantation rat embryo culture using maternal hepatocytes in co-culture.

The post-implantation rat embryo culture technique is employed to study embryotoxic effects of xenobiotic compounds in the absence of the maternal compartment. For compounds biotransformed in vivo the embryo culture technique must be adapted in order to mimick the in vivo effects. In the present study the possibility of co-culturing metabolically active maternal hepatocytes suspended in the standard culture system with rat serum as a medium was investigated. Cyclophosphamide (CP) was used as a model compound as it needs bioactivation to display embryotoxicity. Morphologic and histologic effects were studied. Neither hepatocytes nor CP alone affected embryo development, whereas in the presence of hepatocytes embryotoxicity was observed at 30 micrograms/ml CP. Embryotoxicity was decreased in the additional presence of metyrapone, a monoxygenase inhibitor. Hepatocyte suspensions prepared via slicing or perfusion of livers were equally effective. In conclusion, co-culture of embryos and suspended hepatocytes can be performed under optimal conditions for embryo development and in the presence of biotransforming activity.

Animals↗
PubMed1990

Experience of two teratology information services in Europe.

Teratology Information Services (TIS) are started in different countries in Europe in order to gather available data on exogenous agents, to evaluate their pertinence to human subjects, and to apply this knowledge to specific cases. Most European centers can only be consulted by medical professionals. The experience of two such services (Lyon, France, and Bilthoven, The Netherlands) is described. Attention is given to the task of TIS, risk evaluation, operational methods, and functioning and future developments.

Abnormalities, Drug-Induced↗
PubMed1987

[The importance of health protection of the consumer in relation to veterinary drugs].

The responsibility of the Ministry of Welfare, Health and Cultural Affairs (WVC) and especially the task of the Veterinary Public Health Inspectorate (VI), and the research and advice of the National Institute of Public Health and Environmental Hygiene (RIVM) are described with regard to the Netherlands Veterinary Medicinal Products Act, now and in the future. The registration of these medicines is also necessary for the safety of the consumer; this holds both for the problems related to residues in products of animal origin, and for the problems with respect to bacterial resistance to antimicrobial drugs, because of therapeutic prescription of the same type of drugs in human patients. The admittance to the market of a veterinary drug will only take place after an adequate risk-evaluation with respect to human health, followed by risk-management; the latter implies the admittance policy and its control. The authors have the opinion that the internal quality control and quality assurance during the meat production chain has to be conducted by the producers themselves. The monitoring of this surveillance, and hence the external quality assurance, will remain a governmental responsibility to safeguard products of animal origin.

Animals↗
PubMed1987

Migration and proliferation of primordial germ cells in the rat.

Information about early primordial germ cell (PGC) formation and migration in rats is lacking. In utero developed and in vitro cultivated whole rat embryos were studied on days 10-13 postcoitum (p.c.). The development of the PGCs was investigated in serial sections stained for alkaline phosphatase activity. On postcoital day 10, PGCs were found in the invaginating visceral yolk sac endoderm and at the base of the allantois. At day 11 p.c. PGCs were mostly found in the ventral and lateral gut wall or in the mesenchyme between the gut and the future genital ridges. At day 12 p.c. most of the PGCs (94%) could be localised in the mesenchyme or in the future genital ridges. On postcoital day 13 almost all PGCs had reached the now-well-developed genital ridges. Quantitative measurements showed an increase in the number of PGCs from 84 at day 10 p.c. up to 2,768 at day 13 p.c. Only slight differences were found between in vivo and in vitro embryos with respect to the number of PGCs and their developmental pattern. The in vitro culture of whole rat embryos enables the discrimination between the effects of indirect (maternal) and direct action of PGC-toxic agents.

Animals↗
PubMed1987

Protective immunity against Vibrio cholerae infection in the rabbit.

The DIC model (Duodenal Inoculation with ligation of the Cecum in rabbits) was employed to study experimentally induced cholera and the related protective immunity. Duodenal inoculation (DI) without ligation of the cecum with live V. cholerae organisms did not cause any disease symptom but induced protection against subsequent challenges with homologous and heterologous organisms for up to 24 months. After 30 months this protective immunity began to decrease. A similar protective immunity could be induced by administration of the A- B+ derivative CVD101 of V. cholerae strain 395. This type of experiment can only be done successfully with conventional, healthy rabbits held under low stress conditions. A so-called specific pathogen-free rabbit breed was found to be entirely unsuitable. Duodenal inoculation with heat- or merthiolate-inactivated V. cholerae for a prolonged period of time by means of an intestinal osmotic minipump did not induce protection. Injection of heat-inactivated V. cholerae material into the Peyer's patches sometimes led to protection, suggesting that a thermostable antigen, possibly lipopolysaccharide, is one of the major protective antigens. Duodenal administration of a combination of inactivated V. cholerae serotypes Ogawa and Inaba cells and 1 mg B subunit of the V. cholerae enterotoxin by up to three inoculations protected only 3 out of 12 rabbits against challenge. The results obtained on the rabbit model are discussed in relation to the efficacy of this vaccine in human volunteers and in a recent field test.

Animals↗
PubMed1985

Vibrio cholerae infection and acquired immunity in an adult rabbit model.

We modified the rabbit model for enteric infection by Vibrio cholerae developed by Spira et al. and designated the RITARD (for removable intestinal tie-adult rabbit diarrhea) model (20). Our modification DISC comprises a permanent ligation of the cecum (C) to prevent resorption of the fluid secreted by the small intestine, a temporary ligation of the small intestine (S) to enable the bacteria to colonize, and duodenal inoculation (DI) of the challenge material. The main difference between RITARD and DISC is that in the latter model the challenge material is injected into the duodenum approximately 10 cm distal to the stomach instead of into the jejunum. Four out of 5 V. cholerae strains tested, including 2 serotypes and 2 biotypes, were able to elicit a massive and usually fatal cholera-like diarrhea. The virulence depended strongly on the culturing conditions. One strain, C5, caused fatal diarrhea in a dose of about 1000 organisms, even if the temporary ligation was omitted (DIC model). Other modifications were the DIS and the DI model in which the permanent ligature of the cecum or both ligatures were omitted. Duodenal inoculation of organisms in a dose of 100 X the minimum infective dose (MID) in the DIS or DI model did not cause any disease symptom. However, such inoculations were found to cause protection against subsequent challenges with 100 X MID of homologous and heterologous organisms up to 52 weeks after duodenal inoculation. Subcutaneous injection with classical, whole cell cholera vaccine gave only partial protection of short duration. This model might contribute to the understanding of the pathogenesis of cholera as well as to the improvement of efficacy testing of cholera vaccines.

Animals↗