Toxic exposures introduction

The Toxic Substances Control Act (TSCA) was enacted in 1976 to identify and control toxic chemical ha2ards to human health and the environment. One of the main provisions of TSCA was to estabUsh and maintain an inventory of all chemicals in commerce in the United States for the purpose of regulating any of the chemicals that might pose an unreasonable risk to human health or the environment. An initial inventory of chemicals was estabhshed by requiring companies to report to the United States Environmental Protection Agency (USEPA) all substances that were imported, manufactured, processed, distributed, or disposed of in the United States. Over 50,000 chemical substances were reported. PoUowing this initial inventory, introduction of all new chemical substances requires a Premanufacturing Notification (PMN) process. To be included in the PMN are the identity of the new chemical, the estimated first year and maximum production volume, manufacture and process information, a description of proposed use, potential release to the environment, possible human exposure to the new substance, and any health or environmental test data available at the time of submission. In the 10 years that TSCA has been in effect, the USEPA has received over 10,000 PMNs and up to 10% of the submissions each year are for dyes (382)... 

Introduction Many natural and artificial substances are toxic to humans (and animals). Liquids and solids can be ingested, or exposure can be through the skin, eyes, or other external passages to the body. Where these substances are gaseous or volatile, toxic effects can result from inhalation. As a result ofaccidents and tests, it has been discovered that some of these substances are more toxic than others. Quantification of the degree of hazard has become important in devising appropriate measures for containing these substances. 

Since the introduction of the JECFA safety evaluation procedure, over 900 flavoring substances have been evaluated by JECFA using this procedure. This procedure provides a practical and efficient scientific means to evaluate flavoring substances by integrating knowledge of toxicity, stmcture-activity relationships, structural class, metabolic fate and exposure. 

Epidemiology studies are, of course, useful only after human exposure has occurred. For certain classes of toxic agents, carcinogens being the most notable, exposure may have to take place for several decades before the effect, if it exists, is observable - some adverse effects, such as cancers, require many years to develop. The obvious point is that epidemiology studies cannot be used to identify toxic properties prior to the introduction of a chemical into commerce. This is one reason toxicologists were invented ... 

In the general introduction to the EU test guidelines for toxicity (Part B), the following dehnition is provided Repeated dose/sub-chronic toxicity comprises the adverse effects occurring in experimental animals as a result of repeated daily dosing with, or exposure to, a chemical for a short part of their expected life-span. ... 

An effective anesthetic agent must be easy to use, quickly render the patient unconscious, and not produce any toxicity. Dr. William T. G. Morton first publicly demonstrated the use of ether as an effective anesthetic agent at the Massachusetts General Hospital on 16 October 1846 before a crowd of skeptical physicians. Raymundus Lullius, a Spanish chemist, discovered ether (CH3CH2)20 in 1275. Its hypnotic effects were soon appreciated (and enjoyed by some), but for many decades ether was only used to treat the occasional medical ailment. Even with ether, the success of surgical procedures did not improve until the introduction of antiseptic procedures and infection control some 20 years later. Ether was replaced by cyclopropane in 1929, which was replace by halothane in 1956. While anesthetic agents are desirable for the patient, exposure of hospital staff is highly undesirable and an important occupational consideration. 

The Introduction of Microprocessor-Based Instrumentation for the Measurement of Occupational Exposures to Toxic Substances... 

Since the advent of OSHA (Occupational Safety and Health Administration), tremendous advances have been made in the degree of sophistication and data gathering ability of toxic substance monitoring instrumentation. Traditionally, exposure standards are often limited by the measurement techniques used to determine exposure. The introduction of new, small computers on a chip, particularly those that have an extensive memory and can be programmed, represents a technology that revolutionizes the measurement of occupational exposures, providing more complete and accurate data. A microprocessor-based dosimeter has been developed with this purpose in mind. 

In addition to this Introduction, this report is organized into four chapters. Chapter 2 and Chapter 3 outline the process the subcommittee recommends for evaluating the potential reproductive and developmental effects of exposures to agents. Chapter 2 outlines the principles for evaluating reproductive and developmental toxicity data. The product of that evaluative process is typically an exposure level- called the unlikely effect level (UEL)-that is assumed not to pose... 

Acute inhalation toxicity can be conducted in an exposure chamber. It is recommended, but not required, that nose-only or head-only exposure be used for aerosol studies to minimize oral exposures due to animals licking compound off their fur. For nongaseous pesticides, introduction of the sample in the form of mist or dust becomes a necessity. The animals are exposed for 4 hr and then transferred to other containers for observations for at least 14 d. The median lethal concentration obtained is referred to as inhalation LC30 (Anonymous, 1998). 

In order to assess risk to individuals following dermal exposure to a pesticide, dermal absorption data are often required to convert dermal deposition data to estimates of systemic exposure. These estimates of systemic exposure are then compared with the No Observed Adverse Effect Levels (NOAELs) from oral toxicity studies or limit values (for instance. Acceptable Operator Exposure Levels (AOELs)) derived from these oral data (Bos et at., 1998 Rennen et al 1999). As noted in the introduction, oral studies are generally used because the toxicology database is typically focused on the oral route of exposure. 

Gonadotoxicity of RVX was investigated in chronic experiments for different ways of introduction. Dermal exposure of male rats to RVX demonstrated that general toxic effects were the governing factor of gonadotoxicity. There were no gonadotoxic effects at the level of threshold... 

The toxic nature of some dyes and intermediates has long been recognized. Dermatologists have reported cases of skin reactions suspected to be caused by textile dyes. The positive link between benzidine derivatives and 2-naphthylamine with bladder cancer is also well documented. In fact, these studies prompted the introduction of stringent government regulations to control the exposure of workers to dye dust and the discharge of chemicals, colors, and other effluents. 

Halothane is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane as shown in Figure 16.7 (39/ 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35/000 patients exposed to halothane/ but the risk of this adverse event is greater in females and is increased with repeat exposure/ obesity/ and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures/ and because these patients usually are febrile and demonstrate eosinophilia/ this reaction is suspected... 

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