Bioconcentration,chemical fate,and environmental effects testing under section 4 of the Toxic Substances Control Act

As of December 31, 1988, the U.S. Environmental Protection Agency (EPA) had published 49 Federal Register (FR) notices acknowledging, proposing, or requiring development of bioconcentration, chemical fate, or environmental effects testing data under Section 4 of the Toxic Substances Control Act (TSCA). These FR notices included 5 Decisions Not to Test (DNTs) that acknowledged industry testing, 19 Notices of Proposed Rulemaking (NPRs) that proposed testing by industry, 9 Notices of Final Rulemaking (NFRs), and 2 Consent Orders (COs) that required industry testing as well as 7 proposed and 7 final Negotiated Testing Agreements (NTAs). Two bioconcentration, 12 chemical fate, and 28 environmental effects tests were submitted to the EPA by industry as a result of issuing DNTs. Industry completed 3 bioconcentration, 86 chemical fate, and 151 environmental effects tests after publication of NTAs. Two bioconcentration, 11 chemical fate, and 14 environmental effects tests were completed as a result of publishing NFRs; 1 chemical fate and 5 environmental effects tests were completed under a CO. As of December 31, 1988, a total of 7 bioconcentration, 110 chemical fate, and 234 environmental effects tests had been completed under TSCA Section 4.     

Debating the Controlled Substances Act

In the United States, the basis of modern drug regulation is the Controlled Substances Act (CSA) of 1970. The CSA laid out the authority of the federal government and provided a framework within which all existing and new substances could be regulated on their abuse potential, safety, and medical utility. The debates over the CSA centered on several critical issues: where to place the authority to make scheduling designations, the impact of scheduling on drug research, and defining what constituted drug "abuse" for purposes of scheduling. Passage of the CSA was aided by broad language that provided a kind of "big tent" which could accommodate diverse points of view. A retrospective assessment of the CSA shows it to have greatly expanded federal administrative authority over the nation's drug supply, much as its authors intended. Other impacts of the CSA, however, are much less certain. This article concludes by highlighting the issues and questions that should guide future retrospective research on the efficacy of drug control regimes.     

专题演讲-W3药物和环境毒物的免疫毒性与神经毒性

Toxicity to the immune system encompasses suppression or enhancement of the immune response. Suppression of the immune response can lead to decreased host resistance to infectious agents or tumor cells. Enhancing the immune response can exaggerate autoimmune diseases or hypersensitivity.     

The global political economy of scheduling: the international-historical context of the Controlled Substances Act

This article explains the international context of regulation to control addicting substances that gave rise to schedules. It discusses the impact of scheduling decisions on subsequent national drug control legislation and international drug control negotiations, highlighting how the creation of schedules introduced new incentives and rewards into calculations about the national/international commerce in drugs. In particular, the schedules affected the development and clinical application of psychotropic substances, and the 1971 Convention on Psychotropic Substances receives special focus. The roles of governmental representatives, pharmaceutical company interests, medical researchers, physicians, and pharmacists are highlighted. The article illustrates how debates about scheduling in international treaties over the previous 40 years impacted the creation of the 1970 Controlled Substances Act in the United States and how the constituencies that contributed to constructing the Controlled Substances Act viewed their efforts in a global context.     

Abuse deterrent formulations and the Controlled Substances Act (CSA)

The Controlled Substances Act (CSA) has reduced the diversion of controlled substances at the manufacturing and distribution levels. Recent increased diversion has occurred at the retail level. Levels of diversion and abuse of controlled substances with similar abuse potential and therapeutic indications often parallel availability for medical use, while rates of diversion and abuse may be influenced by factors related to specific products, including their formulations and risk management plans. Abuse deterrent formulations may reduce abuse and attendant adverse health consequences even if the products are diverted. Their development should consider how, to what extent and by whom products containing the targeted substance are abused. It should take into consideration all potential types of abuse including "as is", multiple doses, alternate routes of administration, physical or chemical separation of the active ingredient, compromised extended release mechanisms and abuse in combination with other substances. Industry incentives for developing abuse-resistant formulations include enhanced corporate image and potentially less restrictive scheduling or risk management plans. Scheduling is substance specific, but the CSA includes products/formulations that are differentially scheduled. Issues to be considered for differential scheduling under the CSA include: (1) whether there is legal authority to do so; (2) application of standard scheduling criteria to individual products; (3) product specific data for "eight factor analyses"; (4) development of predictive data and standards accepted by the scientific and regulatory communities; (5) use of predictive data or post marketing surveillance data; (6) international treaty obligations. These issues must be addressed before differential scheduling can be considered.     

The "vine of the soul" vs. the Controlled Substances Act: implications of the hoasca case

In 2006, the Supreme Court paved the way for the sacramental use of a hallucinogen, hoasca, to be imported, distributed and ingested by a religious group. This case has broad implications for religious freedom for using sacramental psychotropics and how such cases might be decided in the future. This article outlines the arguments used both by the church and by the government. It lists the facts of the cases, explains and analyzes the decision, evaluates the likelihood of expansions of religion-based exceptions for entheogen use in light of the Supreme Court's decision and offers a profile for those groups most likely to receive such an exemption.     

Cadmium: Toxic effects on placental and embryonic development

Cadmium is a non-essential trace metal that has strong teratogenic and mutagenic effects in living organisms. The content is more highly enriched in women than in men and can enter the embryo through the placenta and destroy the placenta's morphological structure, resulting in fetal growth restriction. In this report, we review published data linking pregnancy exposure to cadmium to placenta and fetal growth and development toxicity and summarize the related mechanisms. An understanding of how cadmium exposure contributes to placental and fetal development is necessary for the development of prevention and control strategies for fetal development defects caused by cadmium exposure during pregnancy.     

Acrylamide effects on kinesin-related proteins of the mitotic/meiotic spindle

The microtubule (MT) motor protein kinesin is a vital component of cells and organs expressing acrylamide (ACR) toxicity. As a mechanism of its potential carcinogenicity, we determined whether kinesins involved in cell division are inhibited by ACR similar to neuronal kinesin [Sickles, D.W., Brady, S.T., Testino, A.R., Friedman, M.A., and Wrenn, R.A. (1996). Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility. Journal of Neuroscience Research 46, 7-17.] Kinesin-related genes were isolated from rat testes [Navolanic, P.M., and Sperry, A.O. (2000). Identification of isoforms of a mitotic motor in mammalian spermatogenesis. Biology of Reproduction 62, 1360-1369.], their kinesin-like proteins expressed in bacteria using recombinant DNA techniques and the effects of ACR, glycidamide (GLY) and propionamide (a non-neurotoxic metabolite) on the function of two of the identified kinesin motors were tested. KIFC5A MT bundling activity, required for mitotic spindle formation, was measured in an MT-binding assay. Both ACR and GLY caused a similar concentration-dependent reduction in the binding of MT; concentrations of 100 microM ACR or GLY reduced its activity by 60%. KRP2 MT disassembling activity was assayed using the quantity of tubulin disassembled from taxol-stabilized MT. Both ACR and GLY inhibited KRP2-induced MT disassembly. GLY was substantially more potent; significant reductions of 60% were achieved by 500 microM, a comparable inhibition by ACR required a 5 mM concentration. Propionamide had no significant effect on either kinesin, except KRP2 at 10 mM. This is the first report of ACR inhibition of a mitotic/meiotic motor protein. ACR (or GLY) inhibition of kinesin may be an alternative mechanism to DNA adduction in the production of cell division defects and potential carcinogenicity. We conclude that ACR may act on multiple kinesin family members and produce toxicities in organs highly dependent on microtubule-based functions.     

Toxic effects of ultraviolet radiation on the skin

Ultraviolet (UV) irradiation present in sunlight is an environmental human carcinogen. The toxic effects of UV from natural sunlight and therapeutic artificial lamps are a major concern for human health. The major acute effects of UV irradiation on normal human skin comprise sunburn inflammation (erythema), tanning, and local or systemic immunosuppression. At the molecular level, UV irradiation causes DNA damage such as cyclobutane pyrimidine dimers and (6-4) photoproducts, which are usually repaired by nucleotide excision repair (NER). Chronic exposure to UV irradiation leads to photoaging, immunosuppression, and ultimately photocarcinogenesis. Photocarcinogenesis involves the accumulation of genetic changes, as well as immune system modulation, and ultimately leads to the development of skin cancers. In the clinic, artificial lamps emitting UVB (280-320 nm) and UVA (320-400 nm) radiation in combination with chemical drugs are used in the therapy of many skin diseases including psoriasis and vitiligo. Although such therapy is beneficial, it is accompanied with undesirable side effects. Thus, UV radiation is like two sides of the same coin--on one side, it has detrimental effects, and on the other side, it has beneficial effects.     

The Controlled Substances Act: how a "big tent" reform became a punitive drug law

The 1970 Controlled Substances Act was part of an omnibus reform package designed to rationalize, and in some respects to liberalize, American drug policy. While the legislation provided additional resources for law enforcement and a systematic means for regulating the use of most psychoactive drugs, it also did away with mandatory minimum sentences and provided more support for treatment and research. Over the next three decades, and in response to public alarm about drug abuse, the US Congress continuously amended the law to produce a more punitive system of drug control. The amendments, which gave the Drug Enforcement Administration greater control over scheduling and maintenance and which substantially increased penalties for illicit trafficking, transformed the law into the legal foundation of America's "drug war," as the stricter criminal approach came to be known. By the 1980s, the flexibility and innovative spirit of the original Controlled Substances Act (and that of Nixon-era drug strategy generally) had largely disappeared from American drug policy.