Regulatory initiatives for natural latex allergy: US perspectives

The US Food and Drug Administration (FDA) has regulatory authority over foods, human drugs, cosmetics, medical devices, radiological products, biologics, and veterinary products. Among these products, FDA believes that the use of medical devices, including medical gloves, condoms, catheters, and breathing bags, represents the greatest source of natural latex proteins to exposed individuals. A medical device is defined in the Federal Food Drug and Cosmetic Act (FFDCA) as an instrument, apparatus, implement, machine, etc., that is intended for use in the diagnosis or treatment of disease or is intended to affect the structure or any function of the body of a human or other animal, and that does not achieve any of its principal intended purposes through chemical action in the body. This article provides some brief, general background about FDA's medical device regulatory process and then addresses the issue of natural latex allergy. Finally we discuss the steps the Agency has taken to evaluate the magnitude and nature of the problem, and FDA's efforts to assist manufacturers, health professionals, and others in minimizing exposure and sensitization to natural latex proteins in medical devices.     

Evaluation of mutagenicity and carcinogenicity using three-tier system

A three-tier approach to mutagenicity evaluation has previously been proposed [1] with three underlying general principles. (1) No generally mutagenic chemical should be released into the environment or be permitted to be used if there exists a satisfactory non-mutagenic substitute; (2) the extent and rigour of the screening procedures should be related to the extent to which man is, or is likely to be exposed to the agent; (3) a mutagenic substance may be used if the benefits are judged to be great enough to outweigh the hazards and if appropriate controls are exercised. The first tier contains short-term screening tests with sub-mammalian systems, the second tier contains short- and longer-term tests with whole mammals, and the third tier involves a risk-benefit evaluation which may entail further more specialized testing procedures and experiments on the detailed metabolism of the agent in vivo.Such a scheme may in principle be used wherever there exists a long-term hazard for which short-term predicitive tests exist. Carcinogenicity evaluation fits well into a three tier approach and evaluation for carcinogenicity and mutagenicity may be run in parallel with some degree of overlap [2]. Long term carcinogenicity trials fall into tier 2, for example, while tier 1 may include (in addition to mutagenicity) such tests as degranulation of endoplasmic reticulum [3] induction of biphenyl hydroxylase [4] and transformation of cells to malignancy in vitro.The third tier of risk-benefit evaluation involves the determination of risk. This is almost impossible to do in a quantitative manner at the present time. Nevertheless some guidance must be given to the decision-maker, however approximate and surrounded by reservations it may be. One approach is to use the radiation-equivalent dose concept using data from a system that is as closely related as possible to man [1]. Such a result may have some validity for the particular end-point and dose range used. Other end-points and dose ranges may give a different value for radiation equivalence and the weight given to it must be determined by the likely importance of the end-point in constituting a genetic hazard to man. The radiation-equivalent dose is thus a common unit of convenience for chemical mutagens which also has the advantage of being more readily understood by regulators and decision-makers without a genetic background. An example of a tentative and qualified radiation-equivalent calculation has been carried out for the fungicide captan [5]. The use of radiation-equivalent concept by Committee 17 [6] seems to imply a near constancy of radiation equivalent dose values over a wide range of species and end-points. This extensio of the radiation-equivalent concept from its use as an approximate common unit of effect to a philosophy for making extrapolations between widely different species does not seem to be justified at the present time.     

A comparison of two methods for evaluating drug-induced chromosome alterations.

Evaluating the technique and procedure for mutagenicity testing in mammals is a prerequisite to the development of a broad spectrum mutagenic assessment program. Two techniques, chromosome examination and micronucleus scoring, show promise but their applicability for mass screening is uncertain. We determined the slide observation time for these two techniques in mice treated orally, subcutaneously, intravenously, and intraperitoneally with cyclophosphamide (CY). In each instance, we detected a dose-response in less observation time by counting micronuclei in polychromatophilic erythrocytes. The simplicity of the scoring method, the ease of micronucleus identification and the rapidity of scoring all suggest the micronucleus test may be favorably integrated into a mutagenicity screening program.     

化妆品眼刺激试验替代方法标准化与展望

眼刺激试验是化妆品安全评价的主要测试项目,目前正尝试建立代替传统动物实验的体外方法,这些方法处于研发、验证和认可的不同阶段。尽管还没有单一体外试验能完全替代兔眼实验,但系统分析替代方法建立的原理、科学相关性和标准化程度的不同,有助于合理选择运用体外方法指导化妆品眼刺激的标识分类、质量检验、产品开发和机制研究。     

GLP原则在体外毒理学评价实验室的应用

在动物福利运动的推动下,以减少、优化和替代动物试验为核心内容的体外试验系统已成为安全评价不可或缺的组成部分,在药品、化学品、化妆品毒理学评价中起到重要作用。体外试验系统不同于体内动物实验,体外毒理学实验室GLP原则的建立和运行应充分考虑体外试验系统的特殊性。目前我国专业的体外安全评价实验室的建设刚刚起步,还没有可供借鉴的成熟经验。本文从实验室组织、试验系统维护、人员职责、质量管理和运行几个方面,介绍了GLP原则在化妆品体外毒理学检验和评价实验室的应用。     

New EU legislation for risk assessment of GM food: no scientific justification for mandatory animal feeding trials

This commentary focuses on the potential added value of and need for (sub)‐chronic testing of whole genetically modified (GM) foods in rodents to assess their safety. Such routine testing should not be required since, due to apparent weaknesses in the approach, it does not add to current risk assessment of GM foods. Moreover, the demand for routine testing using animals is in conflict with the European Union (EU) Commission's efforts to reduce animal experimentation. Regulating agencies in the EU are invited to respect the sound scientific principles applied to the risk assessment of foods derived from GM plants and not to interfere in the risk assessment by introducing extra requirements based on pseudo‐scientific or political considerations.     

Experience with mutagenicity testing of new drugs: viewpoint of a regulatory agency

Quality and quantity of mutagenicity testing were analyzed for drugs with new active compounds which were submitted for registration in the Federal Republic of Germany from mid 1982 to mid 1986. A large variety of deficiencies was found, applying to selection and number of mutagenicity tests as well as to test performances. Only 65 out of the 144 drugs submitted for registration were tested sufficiently in the initial phase of registration. From 1982 to 1986 this situation has not been changed markedly. Inadequate test performance still remains the main reason for insufficient testing, leading in some cases to artificially positive results. For in vivo tests the selection of test species was mainly motivated by technical reasons and not by characteristics of the test compound. Most of the insufficiencies were eliminated during the second phase of registration. In some cases insufficient mutagenicity testing led to consequences concerning risk-benefit assessment of the drug and its regulation.     

On a Romanian attempt to legislate on medically assisted human reproduction

The paper presents and briefly analyses some of the provisions of a Romanian legislative proposal which arrived at the Presidency for ratification twice, in slightly different forms, and which was rejected twice: the first time at the Presidency in October 2004, and the second at the Constitutional Court in July 2005. The proposal was finally dropped in February 2006. My intention here is to point to some of the most problematic deficiencies of the legislative document in the hope that this may assist with future debates and regulations on assisted reproduction either in Romania or elsewhere. I have isolated the features to be discussed under two headings: (1) whose are the rights to reproduce, that the document claimed to ‘acknowledge, regulate and guarantee’ and (2) what is the status of the embryo, the child and the surrogate mother?     

Overview of mycotoxin methods, present status and future needs

This article reviews current requirements for the analysis for mycotoxins in foods and identifies legislative as well as other factors that are driving development and validation of new methods. New regulatory limits for mycotoxins and analytical quality assurance requirements for laboratories to only use validated methods are seen as major factors driving developments. Three major classes of methods are identified which serve different purposes and can be categorized as screening, official and research. In each case the present status and future needs are assessed. In addition to an overview of trends in analytical methods, some other areas of analytical quality assurance such as participation in proficiency testing and reference materials are identified.     

The toxicological evaluation of mutagenic events

At present no mammalian test system which meets the toxicological requirements is available for routine testing of mutagenicity. Therefore, emphasis should be laid primarily on basic research in this area and not on large-scale screening of possible mutagens with methods known to be inadequate in many respects, if mutagenicity is a major hazard to man, a view certainly not shared by all toxicologists.Furthermore, if carcinogenicity is based on a mutagenic event occurring in somatic cells, the well established tests for carcinogenicity would provide a better way for evaluating irreversible somatic mutations than the tests now suggested for mutagenicity testing.In the present situation a drastic reduction of the noxes men are exposed to would be the most reliable means of preventing a toxicological disaster. We are still in the situation of continuously performing “mass human experiments” and detecting hazards only after considerable harm has been done. Consequently, the goal must be neither to expose a considerable proportion of our population to environmental hazards nor to give drugs to thousands or even millions of healthy people for any reasons whatsoever, unless test systems are available which would allow effective prevention of disaster.     

‘Homework’ and transnational adoption screening in Spain: the co‐production of home and family

We use the transnational adoption screening process as a lens for examining the co‐production of the home and the family in Spain. We propose the term ‘homework’ to describe the efforts of adoption applicants to perform an appropriate home and thus receive approval to adopt. The transnational adoption screening process is a key site of state‐individual interaction for communicating a set of classed, gendered norms. Through that process, participants ratify the authority of professionals to distinguish between adequate and inadequate ways to live. As such, our analysis demonstrates how moral authority is ascribed to material objects, as we document the strong link between ‘appropriate’ housing and growing families as an explanatory factor for the demographic effects of economic crises.     

Regulatory issues concerning the safety, efficacy and quality of herbal remedies

Herbal remedies and alternative medicines are used throughout the world, and in the past herbs were often the original sources of most drugs. Today we are witnessing an increase in herbal remedy use throughout the Western world raising the question as to how safe are these preparations for the unborn fetus? Many women use herbal products during pregnancy. The dilemma facing most regulatory authorities is that the public considers these products as either traditional medicines or natural food supplements. The user sees no reason for regulation. Most countries have laws concerning foods, drugs, and cosmetics, the details of which seldom clearly define to what section of the law and regulations alternative remedies belong. In most countries alternative remedies are regulated as foods, provided that no medicinal claim is made on the label. The global regulatory sector, however, is changing rapidly. The Therapeutic Goods Administration (TGA) in Australia created a Complimentary Medicines Evaluation Committee in late 1997 to address this issue, and Canada has created a new Natural Health Products Directorate in the realigned Therapeutic Products and Foods Branch in 2000. In parallel, the European Agency for the Evaluation of Medicinal Products has drafted test procedures and acceptance criteria for herbal drug preparations and herbal medicinal products. In the US, the Food and Drug Administration classifies these natural products as dietary supplements. Manufacturers must label a dietary supplement thus: “this statement has not been evaluated by the FDA [, and] this product is not intended to diagnose, treat, cure or prevent any disease.” Whether these products are foods or drugs is undecided. To add complexity to this issue, most of the potential deleterious effects of natural products on the unborn may be related to hormonal effects (e.g., phytoestrogens) and nutriceutical drug interactions (e.g., St. John's Wort and antidepressants), rather than direct embryotoxicity per se. We suggest that ensuring quality of herbal products should receive immediate attention by regulatory authorities, before embarking on the more arduous tasks of safety and efficacy. Birth Defects Res B 68:505–510, 2003. © 2003 Wiley‐Liss, Inc.     

Analysis of gyrA mutations in quinolone-resistant and -susceptible Campylobacter jejuni isolates from retail poultry and human clinical isolates by non-radioactive single-strand conformation polymorphism analysis and DNA sequencing

AIMS: The aims of this study were to characterize the molecular variations in the quinolone resistance-determining region (QRDR) of gyrA among quinolone-resistant and -susceptible Campylobacter jejuni isolates originating from foods of animal origin and human infections and to evaluate the suitability of the single-strand conformation polymorphism (SSCP) method as a screening method for molecular characterization of fluoroquinolone resistance. METHODS AND RESULTS: Alterations in QRDR of gyrA from 182 C. jejuni isolates were determined by nonradioisotopic SSCP analysis and direct sequencing. A total of 13 types of nucleic acid sequence combinations within the QRDR of the gyrA gene resulted in 11 different SSCP patterns. All nalidixic acid resistant strains possessed nucleotide substitution at either codon Thr-86 or Asp-90. Silent mutations were detected additionally. Thr-86 to Ile mutation was detected in all 139 ciprofloxacin resistant strains, which showed cross-resistance to nalidixic acid. CONCLUSIONS: The SSCP method is suitable for a molecular screening of quinolone resistant C. jejuni isolates and in combination with DNA sequencing suitable to detect genetic variations of the QRDR of gyrA. SIGNIFICANCE AND IMPACT OF STUDY: This study provides data of the genetic variations of the QRDR of gyrA from C. jejuni isolates of foods and human beings.     

Molecular genetics of DNA repair in higher plants

Damage to DNA occurs in all living things, and the toxicity and/or mutagenicity of the damage products are reduced through the activities of one or more DNA repair pathways. The mechanisms of DNA repair are best understood in microorganisms and mammals, but the field has recently expanded to include both plants and lower animals. These recent advances in our understanding of the molecular and classical genetics of DNA repair in higher plants include such aspects as the repair of UV-induced pyrimidine dimers, the correction of mismatched bases, and the rejoining of double strand breaks.     

Low Efficiency of Short-Term Tests in the Assessment of the Potential Mutagenic Hazard of Chemical Compounds to Mammals

A new method of the efficiency assessment of testing mutagenicity chemical pollutants is proposed. The method is based on the selective information criterion and allows one to compare the prognostic significance of results obtained in both individual tests and test batteries. The efficiency of mutagen detection in mammals was estimated in Ames' test, the in vivo test for cytogenetic abnormalities in rodent bone-marrow cells, and the battery combining both these tests. The level of evidence for mutagenicity was determined for chemicals analyzed in these tests. Based on information obtained during the trials, a low efficiency of the analyzed tests and their battery was inferred.     

Alternative strategies in assuring blood safety: An Overview

Assuring transfusion safety is an essential element of health care in all countries, requiring government commitment, national policy and a legal framework. Fundamental safety strategies include selection of low risk donors, Good Manufacturing Practices in preparation of blood components, and appropriate clinical use including avoidance of unnecessary transfusions. Hemovigilance, including surveillance for known adverse events and sentinel reporting of unexpected adverse events, enhances safety through benchmarking to promote best practices and by enabling rapid responses to new threats. Preventing transmission of infectious diseases is a principal safety concern. Selection of low risk donors includes use of screening questions to elicit risk factors known to be associated with transmissible infections. Laboratory testing for specific infectious disease markers is an established strategy for interdicting contaminated donations. The sensitivity, specificity, and operational convenience of laboratory testing have improved over time and newer technologies are imminent. Donor screening and laboratory testing, while highly effective in reducing risk, cannot eliminate all risk from known agents and must be developed de novo to address emerging infections. In contrast, pathogen reduction technologies offer the possibility for robust inactivation of a broad spectrum of blood transmissible agents and provide an added safeguard against newly emerging infectious threats of most types. Current pathogen reduction methods also inactivate leukocytes, adding safety benefits similar to leukocyte removal and product irradiation. However, to date, concerns about the safety and efficacy of cellular blood components treated by pathogen reduction have prevented approval of these technologies in the U.S. and Canada. FDA is promoting clinical and basic scientific studies to clarify these issues and would consider alternative approaches to assuring blood safety if pathogen reduction technologies are proven to be safe and effective.     

Low efficiency of short-term tests in the assessment of the potential mutagenic hazard of chemical compounds to mammals

A new method of the efficiency assessment of testing mutagenicity chemical pollutants is proposed. The method is based on the selective information criterion and allows one to compare the prognostic significance of results obtained in both individual tests and test batteries. The efficiency of mutagen detection in mammals was estimated in Ames' test, the in vivo test for cytogenetic abnormalities in rodent bone-marrow cells, and the battery combining both these tests. The level of evidence for mutagenicity was determined for chemicals analyzed in these tests. Based on information obtained during the trials, a low efficiency of the analyzed tests and their battery was inferred.     

Proposed rule: current good manufacturing practice in manufacturing, packing, or holding dietary ingredients and dietary supplements

The Dietary Supplement Health and Education Act (DSHEA) was enacted in October 1994 to promote the health of Americans by ensuring easier access to safe dietary supplements. Many supplements such as vitamins, minerals, herbs and amino acids have been reported to be helpful in chronic conditions (i.e., heart disease, cancer and osteoporosis). Under DSHEA, dietary supplements can be marketed without prior FDA approval; the burden is on this agency to show that a marketed dietary supplement is unsafe. However, DSHEA retained the FDA's authority to issue regulations that require the manufacture of dietary supplements be in compliance with current good manufacturing practice (cGMP) standards, which are needed to ensure their quality. Several quality-related concerns of marketed dietary supplements that came to light since the passage of DSHEA prompted the FDA in 2003 to propose rules for cGMP for the manufacture, packaging and holding (storage) of dietary supplements. This review will present the highlights of these proposed rules, focusing on the legislative history of DSHEA, rationale for proposing cGMPs along with a general discussion of the specific requirements. Given the voluminous nature of the specific details, the reader is directed to the pertinent FDA publications for details. In this analysis, selected scientific and legal issues are also discussed to promote a better understanding and implications of these rules.