Robert L. Brent

TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

Radiation Risk to Children From Computed Tomography

Imaging studies that use ionizing radiation are an essential tool for the evaluation of many disorders of childhood. Ionizing radiation is used in radiography, fluoroscopy, angiography, and computed tomography scanning. Computed tomography is of particular interest because of its relatively high radiation dose and wide use. Consensus statements on radiation risk suggest that it is reasonable to act on the assumption that low-level radiation may have a small risk of causing cancer. The medical community should seek ways to decrease radiation exposure by using radiation doses as low as reasonably achievable and by performing these studies only when necessary. There is wide agreement that the benefits of an indicated computed tomography scan far outweigh the risks. Pediatric health care professionals’ roles in the use of computed tomography on children include deciding when a computed tomography scan is necessary and discussing the risk with patients and families. Radiologists should be a source of consultation when forming imaging strategies and should create specific protocols with scanning techniques optimized for pediatric patients. Families and patients should be encouraged to ask questions about the risks and benefits of computed tomography scanning. The information in this report is provided to aid in decision-making and discussions with the health care team, patients, and families.

Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child.

Arava™ (leflunomide) is a pyrimidine synthesis inhibitor used in the treatment of active rheumatoid arthritis (RA). The chemical name for leflunomide is N-(49-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. Because the drug has been successful in the treatment of rheumatoid arthritis, it is being widely prescribed. In spite of the clear warning that the drug should not be prescribed for pregnant women, approximately 30 women have become pregnant while taking leflunomide as of December 1999. This commentary was prepared to aid teratology counselors and genetic counselors who might be contacted by physicians or patients about the risk of leflunomide exposure during pregnancy. Before the subject of risk is discussed, it is important to understand the results of preclinical testing, phamacokinetic studies, and clinical studies that are available.

Are female sex hormones teratogenic

An analysis of available epidemiologic data leads the present reviewers to conclude that the use of exogenous hormones during human pregnancy has not been proved to cause developmental abnormality in nongenital organs and tissues. This conclusion is further supported by the animal laboratory data. The preponderance of evidence at this writing indicates a lack of causal association between hormonal use during pregnancy and nongenital malformation of the offspring. The quality of the epidemiologic data does not, at this time, permit a definitive conclusion that sex hormones during pregnancy may not, under as yet to be defined conditions, have some adverse effect on human prenatal development. If there are increased risks of nongenital malformations associated with the administration of certain sex steroids, the risks are very small, may not be causal, and are substantially below the spontaneous risk of malformations. In spite of the present degree of uncertainty, the clinical, epidemiologic, and laboratory data do permit the formulation of a rational approach to handling problems related to sex steroid usage and exposure in pregnant women.

Evaluation of the reproductive and developmental risks of caffeine

A risk analysis of in utero caffeine exposure is presented utilizing epidemiological studies and animal studies dealing with congenital malformation, pregnancy loss, and weight reduction. These effects are of interest to teratologists, because animal studies are useful in their evaluation. Many of the epidemiology studies did not evaluate the impact of the “pregnancy signal,” which identifies healthy pregnancies and permits investigators to identify subjects with low pregnancy risks. The spontaneous abortion epidemiology studies were inconsistent and the majority did not consider the confounding introduced by not considering the pregnancy signal. The animal studies do not support the concept that caffeine is an abortafacient for the wide range of human caffeine exposures. Almost all the congenital malformation epidemiology studies were negative. Animal pharmacokinetic studies indicate that the teratogenic plasma level of caffeine has to reach or exceed 60 µg/ml, which is not attainable from ingesting large amounts of caffeine in foods and beverages. No epidemiological study described the “caffeine teratogenic syndrome.” Six of the 17 recent epidemiology studies dealing with the risk of caffeine and fetal weight reduction were negative. Seven of the positive studies had growth reductions that were clinically insignificant and none of the studies cited the animal literature. Analysis of caffeines reproductive toxicity considers reproducibility and plausibility of clinical, epidemiological, and animal data. Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth retardation. Pharmacokinetic studies markedly improve the ability to perform the risk analyses. Birth Defects Res (Part B) 92:152–187, 2011.

The Potential Adverse Health Effects of Dental Amalgam

There is significant public concern about the potential health effects of exposure to mercury vapour (Hg0) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg0, evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects.Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg0 is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg0 released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg0 and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg0 levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20–30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Production of Congenital Malformations Using Tissue Antibodies. I. Kidney Antisera.

Summary Rabbit anti-rat kidney sera, in a prescribed dosage, injected intravenously into pregnant rats on the 8th day of gestation. resulted in severe congenital malformations in 100% of the fetuses. Larger doses caused complete fetal resorption. These antisera may produce teratogenesis by interfering with placental function.

Bendectin: Review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen

OBJECTIVE to review the extensive literature pertaining to the reproductive and teratogenic effects of Bendectin and the opinions of the scientific experts for the defense and plaintiff. These data were evaluated with regard to the reproductive risks of Bendectin providing a scientific framework for evaluating the views of the experts in the Bendectin litigation. DESIGN the Bendectin literature was primarily obtained from articles cited in Research Alert of the Institute for Science Information. Other articles were obtained from Medline, review articles, and colleagues. An attempt was made to be all-inclusive, citing and reviewing all articles related to each subject being discussed. The literature includes epidemiologic studies, animal studies, in vitro studies, and basic science articles related to the principles of teratology and reproductive toxicology. Review articles, meta analyses, editorials, commentaries, articles in the press, and case reports were also included. METHODOLOGY the methodology utilized for the evaluation of Bendectin teratogenicity was presented. It consists of a five-part analysis of epidemiologic studies, secular trend analysis, animal studies, dose-response relationships, and biologic plausibility. CONCLUSION the five-part analysis of Bendectin reproductive effects indicates that therapeutic use of Bendectin has no measurable teratogenic effects. Presentations by many of the plantiffs experts failed to meet the scientific standards that should be expected of knowledgeable scientists and contributed to the persistence of Bendectin litigation.

The embryonic rat parietal yolk sac: Changes in the morphology and composition of its basement membrane during development☆

Abstract The basement membrane (Reicherts membrane) of the entire capsular portion of the parietal yolk sac of rat embryos was examined both morphologically and chemically at various stages of gestation. The overall microscopic and compositional analyses showed Reicherts membrane to be typical of basement membranes isolated from other tissues and species. However, with increasing gestational age (from 11.5 to 17.5 days) a number of changes involving Reicherts membrane were noted: 1. The thickness increased rapidly then declined, while the surface area increased tenfold; 2. The total protein content increased twenty-fold while the collagen content increased eight-fold. As a result, the relative collagen content declined significantly; 3. The changes in the amino acid and carbohydrate composition were consistent with the latter finding. The observations listed above were evaluated in light of their possible relevance to an understanding of the morphogenesis of basement membranes during development, and to the possible mechanisms involved in pathogenesis of basement membrane dysfunction.

Persistent jaundice in infancy

I have collected the opinions of a number of pediatricians and pediatric pathologists regarding the causes of persistent jaundice during infancy. Most would discard the term “inspissated bile syndrome”, but there is less unanimity regarding the meaning of “neonatal hepatitis”, the significance of giant cells in the liver, and the value of needle biopsies. The many causes of infantile jaundice are mentioned, and hepatic physiology during the neonatal period is discussed. Finally, a program is outlined for the study of the infant with persistent jaundice. The value of the determination of the excretion of radioactive rose bengal in differentiating complete biliary atresia from other causes of jaundice is emphasized.