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The European Community must become a fully integrated market by 1992. The differing national requirements for pharmaceutical product registration constituted a barrier, unresolved by the creation of a nonmandatory process of mutual recognition of pharmaceutical licences. Interested parties have been asked to recommend measures to abolish the remaining barriers. The principle sought is that a single authorisation shall afford simultaneous approvals in all member states. Considerable debate has taken place but there is no clear concensus. Recommendations include mandatory mutual recognition, a central FDAlike European Agency and a combination of both. A tripartite solution is recommended. This is a sharing of responsibility between the National Agencies and a central European body. A small European Secretariat would coordinate activities and, using expert consultants, hear and resolve appeals. The National Agencies would share the licence application assessments and the CPMP would be responsible for, among other things, the education standards of Agency personnel.

With the definition of teratogenicity expanded in terms of the developmental stages when an agent acts and the types of developmental anomalies induced, the concept of developmental toxicity has been established. The examination of functional developmental disorders including behavior has become one of the most important items for the evaluation of developmental toxicity of chemicals, especially pharmaceutical drugs. The guidelines for developmental toxicity testing of drugs in Japan stress the need for examination of growth and development including behavior and fertility on the postweaning offspring. The outline of the Japanese guidelines is presented and it is emphasized that studies should be done as research and include self evaluation of the scientific truth of the experiment and extrapolation to humans. In addition, the activities of the Behavioral Teratology Meeting, a satellite meeting to the Japanese Teratology Society, are introduced and enquête surveys of the Japan Pharmaceutical Manufacturers Association and collaborative studies for the standardization of learning tests in Japan are briefly presented.

This study outlines the attempts of four states (Louisiana, Kansas, Wisconsin, and Michigan) to restrict anorectic prescriptions. The actions in these four states exemplify the various mechanisms used in regulating anorectics, ranging from educational efforts to legislative enactments. We examine the evidence used in promulgating these policies and review some of the current literature on the safety and efficacy of anorectics. Despite the existence of evidence demonstrating the safety and efficacy of anorectics, the states seem to be moving toward more severe restrictions, in contrast to the federal regulatory agencies.

The situation in the region of Aix la Chapelle with its borders towards The Netherlands and Belgium has presented us with increasing problems in drug and narcotic delinquency during recent years. Because of the revised law on narcotic drugs in 1982 and recent decisions by the German Federal Supreme Court, forensic toxicologists are expected not only to define drugs qualitatively as well as quantitatively, but also to provide expertise on problems of effective doses, pharmacokinetics, toxicity and tolerance development with various narcotic drugs. Based on our own experience in this special forensic field, as well as on the data compiled by investigation authorities, our analytical findings are presented with regard to toxicological interpretation and the legal consequences.

An analysis of several agencies' risk assessments reveals that the present conservative approach through several stages of estimates of amounts of regulated substances, the exposure levels, and cancer risks often tends to distort the actual final regulation. Changes in this process are desirable and possible and would reduce overestimation of cancer risk assessments. These possible changes are discussed.

In reaching a regulatory decision on the use of pesticides with carcinogenic potential, it is of great importance to investigate the extent of dermal exposure and absorption of a pesticide to users and field workers. By applying this information, along with the appropriate carcinogenicity categorization of a pesticide, a reasonably sound regulatory decision can be derived. Seven pesticides were selected, based on adequacy of tumor data, and were taken through the tumor evaluation system as reported in Part I 1984, Regul. Toxicol. Pharmacol. 4, 355-360). A step-by-step analysis on how a regulatory decision is reached on each pesticide by the EPA and CDFA was discussed.

Between 1982 and 1983, the Commission on Approval for Marketing Medications of the French government made 76 negative decisions based on problems with clinical trials. In 21 instances, the reasons for a temporary negative decision could be resolved from data already on hand or readily available. More serious problems resulted in requests for new studies having better controls, better management of ancillary therapy, more participants, or lasting longer. Indications that denial of the application is likely or outright refusals to grant approval were based on failure to demonstrate efficacy and concerns about toxicity. Analysis of the reasons for negative decisions can ameliorate the clinical trials submitted in support of an application for marketing approval. Improving the design and conduct of clinical trials based on correcting the defects discussed here would benefit the sciences of drug development, regulation, and patient care.

Many events or studies, such as the Minimata episode, during the past three decades have shown that prenatal insults can have lasting effects on the postnatal functioning of the offspring. These have been duplicated in animal models, and animal studies have been extended to other compounds with the eventual goal of being able to establish the risk in humans of neurological damage a priori from prenatal exposures. However, behavioral tests are not standardized with many of them lacking sensitivity, and are so vulnerable to environmental factors, that little confidence can be placed in their ability to predict risk to the human at this time. More research is needed to develop better tests and an understanding of their significance to humans before they are useful in regulatory toxicology.

Interpretive difficulties can be expected when molecular biology and modern genetics are applied to the safety evaluation of chemicals. Experience, in a regulatory setting, with evaluating the results of short term tests, such as Ames' mutagenicity assay using Salmonella typhimurium (Ames' assay), shows that the traditional toxicological paradigm for interpreting and evaluating the results of such tests is less than adequate. The considerable importance of a negative test outcome to the public health as well as to the course of the commercial development of a potentially useful chemical places special demands on both the investigator and the regulatory reviewer for an understanding of Ames' assay. The adequate design, conduct, interpretation, and evaluation of the outcomes of this assay require a knowledge of the chemical properties of the test agent, an understanding of the scientific basis of the test, and an appreciation of the extent to which modifications of the assay can alter the outcome. The investigator and the regulatory reviewer use the same considerations to determine the adequacy of the test design and of the test results. However, a fundamental difference exists between how they interpret results and how they view the outcome. Results from a study comparing activation systems from food animal and laboratory animal sources are used to illustrate the complexity of using safety data from a genetic test. A framework is developed to suggest how to accommodate the points of view of the investigator and the regulatory reviewer in evaluating these data.

'Designer drugs' are substances intended for recreational use which are derivatives of approved drugs so as to circumvent existing legal restrictions. The term as popularised by the lay press lacks precision. Contrary to the popular belief that 'designer drugs' are original creations, the majority of these agents are 'borrowed' from legitimate pharmaceutical research. They merely represent the most recent developments in the evolution of mind-altering chemicals. The most extensively studied class of psychoactive compounds is the phenylethylamines (mescaline analogues). This class includes catecholamines, therapeutic agents and numerous illicit derivatives. Subtle alterations of the phenylethylamine molecule give rise to a spectrum of pharmacological properties ranging from pure sympathomimetic stimulation to primarily psychoactive effects. Although most of these compounds are only of historical interest, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA) continue to be used recreationally. Many deaths have been ascribed to this class of compounds. In overdose the differences between these compounds blur and the clinical presentation is similar to that of amphetamine overdose characterised by tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis, agitation, muscle rigidity, and hyper-reflexia. Death usually results from arrhythmias, hyperthermia or intracerebral haemorrhage. Treatment is aggressive and supportive with careful attention to temperature, blood pressure and seizure control. Synthetic opioid derivatives, which represent the second major class of 'designer drugs', are derivatives of fentanyl (e.g. alpha-methylfentanyl, 3-methylfentanyl) or pethidine (meperidine) and are extremely potent compounds responsible for numerous overdose deaths. Attempts to synthesise pethidine have resulted in the accidental production of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a compound which is metabolised in the brain by the monoamine oxidase system to a toxic intermediate (MPP+) which selectively destroys the sustantia nigra, resulting in the rapid onset of severe Parkinsonian symptoms. Naloxone will antagonise the opiate effects of this drug class, although high doses may be required. Arylhexylamines constitute the third class of 'designer drugs'. The predominant member of this class is phencyclidine (PCP), a derivative of the anaesthetic ketamine. This unique class of psychoactive agents exhibits broad and complex pharmacological effects.(ABSTRACT TRUNCATED AT 400 WORDS)

The safety or risk assessment of a pharmacotherapeutic agent begins early in its development and continues throughout its use cycle. The practice of pharmacoepidemiology is the art of using the sciences and the tools of science to generate information about pharmaceutical outcomes, including associated risks, in the postmarketing environment. A pharmacoepidemiologist must be capable of functioning with a matrix constructed of three components: a knowledge base, a conceptual framework, and an interpretive framework. From this perspective one can establish surveillance schemes, or understand a posed research question, select strategies, apply methodologies, and interpret the results of purposeful investigations. When conveyed to the risk manager, appropriately interpreted results of a properly conducted risk assessment can be used in regulatory decision making. Seven case studies are presented as examples of this approach.