Anthony R. Scialli

Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease

Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women. It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for leprosy and later, multiple myeloma. In rural areas of the world that lack extensive medical surveillance initiatives, thalidomide treatment of pregnant women with leprosy has continued to cause malformations. Research on thalidomide mechanisms of action is leading to a better understanding of molecular targets. With an improved understanding of these molecular targets, safer drugs may be designed. The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in the biochemical pathways of limb development. In celebration of the Society of Toxicologys 50th Anniversary, which coincides with the 50th anniversary of the withdrawal of thalidomide from the market, it is appropriate to revisit the lessons learned from the thalidomide tragedy of the 1960s.

Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process.

OBJECTIVE To develop recommendations for the medical and surgical care of women who present with chronic pelvic pain (CPP) and are likely to have endometriosis as the underlying cause. DESIGN An expert panel comprised of practicing gynecologists from throughout the United States and experts in consensus guideline development was convened. After completion of a structured literature search and creation of draft algorithms by an executive committee, the expert panel of >50 practicing gynecologists met for a 2-day consensus conference during which the clinical recommendations and algorithms were reviewed, refined, and then ratified by unanimous or near-unanimous votes. PATIENT(S) Women presenting with CPP who are likely to have endometriosis as the underlying cause. MAIN OUTCOME MEASURE(S) None. CONCLUSION(S) Chronic pelvic pain frequently occurs secondary to nongynecologic conditions that must be considered in the evaluation of affected women. For women in whom endometriosis is the suspected cause of the pain, laparoscopic confirmation of the diagnosis is unnecessary, and a trial of medical therapy, including second-line therapies such as danazol, GnRH agonists, and progestins, is justified provided that there are no other indications for surgery such as the presence of a suspicious adnexal mass. When surgery is necessary, laparoscopic approaches seem to offer comparable clinical outcomes to those performed via laparotomy, but with reduced morbidity. The balance of evidence supports the use of adjuvant postoperative medical therapy after conservative surgery for CPP. There is some evidence that adjuvant presacral neurectomy adds benefit for midline pain, but currently, there is inadequate evidence to support the use of uterosacral nerve ablation or uterine suspension. Hysterectomy alone has undocumented value in the surgical management of women with endometriosis-associated CPP.

A Two-Year Randomized Weight Loss Trial Comparing a Vegan Diet to a More Moderate Low-Fat Diet

Objective: The objective was to assess the effect of a low‐fat, vegan diet compared with the National Cholesterol Education Program (NCEP) diet on weight loss maintenance at 1 and 2 years.

Teratogen update: Methotrexate

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.

Diet and Sex-Hormone Binding Globulin, Dysmenorrhea, and Premenstrual Symptoms

Objective To test the hypothesis that a low-fat, vegetarian diet reduces dysmenorrhea and premenstrual symptoms by its effect on serum sex-hormone binding globulin concentration and estrogen activity. Methods In a crossover design, 33 women followed a low-fat, vegetarian diet for two menstrual cycles. For two additional cycles, they followed their customary diet while taking a supplement placebo pill. Dietary intake, serum sex-hormone binding globulin concentration, body weight, pain duration and intensity, and premenstrual symptoms were assessed during each study phase. Results Mean (± standard deviation [SD]) serum sex-hormone binding globulin concentration was higher during the diet phase (46.7 ± 23.6 nmol/L) than during the supplement phase (39.3 ± 19.8 nmol/L, P < .001). Mean (± SD) body weight was lower during the diet (66.1 ± 11.3 kg) compared with the supplement phase (67.9 ± 12.1 kg, P < .001). Mean dysmenorrhea duration fell significantly from baseline (3.9 ± 1.7 days) to diet phase (2.7 ± 1.9 days) compared with change from baseline to supplement phase (3.6 ± 1.7 days, P < .01). Pain intensity fell significantly during the diet phase, compared with baseline, for the worst, second-worst, and third-worst days, and mean durations of premenstrual concentration, behavioral change, and water retention symptoms were reduced significantly, compared with the supplement phase. Conclusion A low-fat vegetarian diet was associated with increased serum sex-hormone binding globulin concentration and reductions in body weight, dysmenorrhea duration and intensity, and premenstrual symptom duration. The symptom effects might be mediated by dietary influences on estrogen activity.

Folic acid in early pregnancy: a public health success story

Folate is a water‐soluble B vitamin that must be obtained in the diet or through supplementation. For > 50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.—Običan, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. Folic acid in early pregnancy: a public health success story. FASEB J. 24, 4167–4174 (2010). www.fasebj.org

Medical and Surgical Therapies for Pain Associated with Endometriosis

Endometriosis is a common condition for which a number of treatments have been proposed. Medical treatments are based on the hormonal responsiveness of endometriosis implants. These therapies include progestins (with or without estrogens), androgens, and gonadotropin-releasing hormone (GnRH) analogs. Surgical treatments may include hysterectomy with oophorectomy or organ-sparing surgery involving ablation or resection of visible lesions of endometriosis and restoration of pelvic anatomy. There are no studies that directly compare the effectiveness or adverse effects of medical therapy and surgical therapy. Studies on medical therapy compare different treatments with placebo or with other active treatments. Hormone-based therapies for endometriosis show 80%-100% effectiveness in relief of pelvic pain over a 6-month course of therapy. Serious adverse outcomes after medical therapy are unusual. Studies on surgical therapy are largely anecdotal, with noncomparative reports on a variety of surgical methods. A few comparative surgical studies have been reported. Because of the noncomparative nature of many of the surgical studies, the use of combinations of surgical procedures and techniques in the reported studies, and the reporting of results from surgeons with an unusually high level of technical skill, the gynecological practitioner has little basis in the literature for assessing the optimum surgical approach. Surgical complications are believed to be underreported and may be related to how aggressive a surgical procedure is undertaken.

The challenge of reproductive and developmental toxicology under REACH.

The European Unions REACH regulation has explicit requirements for reproductive and developmental toxicity data on all substances manufactured in or imported into the European Union at > or = 10 metric tons/year. Meeting the data requirements with whole-animal testing could result in the use of almost 22 million vertebrate animals for the registration of existing chemicals and cost up to several hundred thousand dollars per registered substance. The requirement for financial and animal resources can be reduced by the use of in vitro testing, quantitative structure-activity relationship models, and grouping of related substances. Although REACH strongly encourages these methods of avoiding vertebrate animal testing, it does not appear that in vitro testing or quantitative structure-activity relationship analysis will be able to replace whole-animal reproductive and developmental toxicity testing. Grouping of related compounds offers the possibility, perhaps in conjunction with in vitro testing and structure-activity analysis, of reducing vertebrate animal testing provided there is sufficient information on the related compounds and sufficient reason to believe that the related compounds will have similar toxicological properties. The designation of a substance as a reproductive or developmental toxicant follows criteria that do not consider the dose level of the substance at which reproductive or developmental effects occur, as long as excessive generalized toxicity does not occur. This method of labeling substances without consideration of effective dose level does not provide information on the actual risk of the chemical. Designation of a substance as a reproductive or developmental toxicant may have important implications under REACH and can be expected to result in the need to obtain authorization for marketing of the substance in the European Union.

Apparent lability of neural tube closure in laboratory animals and humans

Neural tube defects (NTDs), a set of structural abnormalities affecting the brain, spinal cord, and the skeletal and connective tissues that protect them, are common malformations among humans and laboratory animals. The embryogenesis of the neural tube is presented to convey the complexity of the phenomenon, the multiplicity of requisite cellular and subcellular processes, and the precise timing of events that must occur for successful neural tube development. Interruption, even transitory, of any of these intricate processes or disruption of an embryos developmental schedule can lead to an NTD. The population distribution of human NTDs demonstrates that genetic predisposition functions in susceptibility to NTDs. Data from animal studies support these concepts. NTDs are common outcomes in developmental toxicity safety assessments, occurring among control and treated groups. Numerous agents have caused increased levels of NTDs in laboratory animals, and species with shorter gestational periods appear more prone to toxicant-induced NTDs than those with longer gestations. Data from post-implantation whole embryo culture, although not predictive of human risk, are useful in studying neurulation mechanisms and in demonstrating the importance of maintaining embryonic schedules of development. We conclude that the concept that NTDs are produced by only a few toxicants that selectively target the developing nervous system is untenable. Rather, the combination of the time in gestation that an agent is applied, its dose, and its ability to disrupt critical processes in neurulation leads to NTDs. We further conclude that, because of both the relatively high prevalence and the multifactorial nature of NTDs, the mere occurrence of an NTD is insufficient for inferring that the defect was caused by an exogenous agent.

An overview of male reproductive studies of boron with an emphasis on studies of highly exposed Chinese workers.

Boron treatment of rats, mice, and dogs has been associated with testicular toxicity, characterized by inhibited spermiation at lower dose levels and a reduction in epididymal sperm count at higher dose levels. The no-adverse-effect level for reproductive effects in male rats is 17.5mg B/kg bw/day. Earlier studies in human workers and populations have not identified adverse effects of boron exposure on fertility, but outcome measures in these studies were relatively insensitive, based mainly on family size and did not include an evaluation of semen end points. A recent study of nearly 1000 men working in boron (B) mining or processing in Liaoning province in northeast China has been published in several Chinese and a few English language papers. This study included individual assessment of boron exposure, interview data on reproductive experience and semen analysis. Employed men living in the same community and in a remote community were used as controls. Boron workers (n=75) had a mean daily boron intake of 31.3mg B/day, and a subset of 16 of these men, employed at a plant where there was heavy boron contamination of the water supply, had an estimated mean daily boron intake of 125 mg B/day. Estimates of mean daily boron intake in local community and remote background controls were 4.25mg B/day and 1.40 mg/day, respectively. Reproductive outcomes in the wives of 945 boron workers were not significantly different from outcomes in the wives of 249 background control men after adjustment for potential confounders. There were no statistically significant differences in semen characteristics between exposure groups, including in the highly exposed subset, except that sperm Y:X ratio was reduced in boron workers. Within exposure groups the Y:X ratio did not correlate with the boron concentration in blood, semen and urine. In conclusion, while boron has been shown to adversely affect male reproduction in laboratory animals, there is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers.