Humane approches to toxicological evaluations of industrial chemicals

Разделы БиологияИностранные языки
Тип

Работа

Формат Microsoft Word
Язык Английский
Загрузить архив:
Файл: ref-22970.zip (40kb [zip], Скачиваний: 200) скачать

NIZNHNY   NOVGORODUNIVERSITY

DEPARTMENT OF ECOLOGY

Summary

HUMANE APPROCHES

TO TOXICOLOGICAL EVALUATIONS

OF INDUSTRIAL CHEMICALS

Made by Loginov V. V.

Scientific advisor

d. b. s., prof. Gelashvili D. B.

NIZHNYNOVGOROD, 1999

There are millions of chemical substances recorded in the scientific literature with many more being added annually through the endeavors of chemists in industry and academia (Tаble 1). Tens of thousands of these substances are used in commerce, as demonstrated by the publication of inventories in the European Economic Community under the Sixth Amendment to the Dangerous Substances Directive and in the United States through the Toxic Substances Control Act (TSCA).

The enormous growth of the chemical industry, coupled with the potential for increased exposure of the population to chemicala, has generated growing public concern and an awareness of the need for correct safety aascsfunent. The toxicological assessment, therefore, of the potential health hazards posed by chemical substances to which humans and animals may be directly or indirectly exposed Is a rational requirement of civilized society.

TABLE 1 Chemical Substances Known

Group

Approximate number

Documened chemicals

(Chemical Abctracts)

7,000,000

Increase per annum

400,000

EINECS (European Inventory of Existing

Commerical Chemical Substances)

95,000

ECOIN (European Core Inventory)

34,000

Known drugs

4,000

Known pesticides

1.500

Over the last 40 years or so, the use of toxicology as a predictive science has developed immensely. This growth has been stimulated by an increasing amount of legislation that ensures that relevant toxiclty studies, which include whole-animal studies, are completed on a vari­ety of chemical substances. Theknowledge of whether a chemical substance has the potential to poison a biological system, cause irritation on contact with the external tissues or cause an allergic response, Is imiwrtant in establishing a safer environment. An awareness of these properties assists society in ensuring correct and safe procedures when people or animals are exposed to chemicals.

Trade in chemicals is international, and therefore understanding the hazards of chemical substances and identifying those hazards on the label requires an international language of hazard warning. Acute toxic effects derived from animal studies have been the subject of standardization for classification and labeling for many years. The language of the label-TOXIC, VERY TOXIC, HARMFUL, IRRITANT, CORROSIVE-is understood by the international community.

While society demands health and safety as prerequisites for the development, manufacture, and use of chemical substances, society is also concerned     with the welfare and humane treatment of the labora­tory animals used in toxiclty testing. This, of course, poses a potential paradox since the complete assessment of the toxicity of chemical sub­stances involves the use of laboratory animals. Codes of practice have been established in many countries to promote humane procedures. The Organisation for Economic Co-operation and Development (OECD) haa made enormous progress in standardizing toxicological testa to reduce barriers to trade caused by varying protocol requirements between nations, and this has had a significant influence in reducing the number of animals used in toxicological studies. The use of live animals as experimental models is not in itself inhumane, although this view is not shared by everyone.

In vitro systems that avoid the use of live animals have been developed for predicting the mutagenic, and possibly carcinogenic, potential of chemical substances, one such Is the Salmonella typhimurium reverse mutation assay (Ames test). This has stimulated many toxicologists, biologists, pharmacologists and biochemists to consider whether alternative in vitro/ex vivo procedures could minimize the need for whole-animal studies in other areas of toxicology.

A primary objective for achieving general acceptance of any in vitro alternative to an animal model for the assessment of potential risk to humans and the environment is to have it accepted by regulatory authorities as a recognized assessment of a toxic property; nowadays there are very few circumstances in chemical manufacture, marketing, transportation, and use that do not come under the auspices of a government department somewhere in the world.

In short, in vitro alternatives need to satisfy scientific criteria for their acceptability and need to satisfy the international regulatory community that their use will not compromise assessment of risk or pose serious problems to international trade in chemicals.

1. OCULAR TOXICITY

The eye is one of the most valuable and vulnerable of sense organs (Albino rabbits are used in the test). Dusturbance of vision, injury to the eye, or even loss of sight due to chemical or phisical damange must be recognized as a most traumatic experience. It is the abhorrence of such events that necessitates the testing of chemicals in order to reduce, and hopefully prevent, their occurrence in humans. This method is the basic for most eye irritation testing today. New chemicals and mixtures of chemicals pose a potential eye hazards to humans. The nature of the hazards needs to be assessed because warnings about the potential harm that a chemical can do to the eye only have credence if they are based on valid information. Labeling all chemicals as hazardous would substantially lessen the benefit of the warning label. Convincing workes and customers that a hazards exicts and that there is a need for special care, including the use of protective eyeglasses or goggles, has to be related to good extrapolation from suitable model systems. The rabbit eye test has its liminations, but in our view it is still the best practical way of assessing ocular damage and can be conducted using a humane approach.

2. SYSTEMIC TOXICITY

In testing for acute systemic toxicity, it is our opinion that in vitro test systems are unlikely to replace in vivo studies. The principle of the test method and procedures generally recommended have been reviewed by many, recently by Organisation for Economic Co-operation  and Development. The rat and mouse are the species of choice because they are able to display a full range of clinical signs of toxicity. The test substance is administered by the most appropriate route (either oral, dermal, or inhalation) to small groups of animals at a range of draduated doses. The formulations of substance and volume administered are standardized as far as possible to avoid the confounding effects of minor protocol variation. Acute systemic toxicity studies assess the relationship between the dose of a substance and adverse effects, its toxicity relative to other substances of know toxicity, the specificclinical sings of toxicity, the physiological systems affected, and often an indication of the mode and potential mechanism of toxic action. Such information may help the clinical to diagnose and treat adverse effects when they occur in humans using specific antidotes. The humane approach employed in most industrial laboratories is he use of the minimum number of experimental animals and the use of euthanasia when toxic effects are detected. In our own laboratory, with experience of a number of different types  of industrial chemicals, many substances are defined adequately by a limit dose or rangefinding study. Indeed, following acute exposure, a relatively small number of substances produce observable adverse systemic effects (Table 2).

TABLE 2

Toxic Categories Following Acute Oral and Dermal   Dosing Studies in the Rat

Oral

Category

Dermal

65%

Low toxicity

66%

(>2000 mg/kg)

(>2000 mg/kg)

29%

Harmful

24%

(200-2000 mg/kg)

(400-2000 mg/kg)

5%

Toxic

9%

(25-200 mg/kg)

(50-400 mg/kg)

0.8 %

Very toxic

0.9 %

(<25 mg/kg)

(,50 mg/kg)

The use of fewer laboratory animals, coupled with a less rigidadherence to the need for statistical precision, is a rational approach that will allow assessment of toxicity hazard and heme prevent human suffering.

3. CUTANEOUS TOXICITY

Skin contact is probably the most common form of exposure to industrial chemicals.The most common in vivo approach to determine such potential is based on the method of Draize et al. In the Draize skin test the animal of choice is the albino rabbit. The skin, like many other organs, is complex is born structure and function. Substances that interact with this tissue can produce different toxic effects. The skin represents tissue that will allow more readly the development of a variety of in vitro and ex vivo systems to assessirritancy and corrosivity. However, the complexity of the immunological system means that contact allergy may not be as readily stadied using in vitro tecniques.

The preceding section of this chapter have deal with the areas of ocular toxicity, acute sustemictoxicity, and cutaneous toxicity, and a common theme has emerged. There is, in our opinion, no immediate likelihood of in vitro alternatives replacing laboratory animals in the assessment of acute effects caused by chemical substances.

Society demands of the toxicologist a high degree of certainty in determining health hazards, with a minimal tolerance of error. Toxicologists, therefore, need to be cautious that, in their search for alternatives to laboratory animals, they do not reduce the predictive quality of toxicological assessment to the point where people will be put at risk.

Selection of a hazard label is particularly dependent on knowing the relative                                   systemic toxicity through the estimation of the median lethal dose (LP50) and the irritant class. The vast majority of chemicals have been classified by data derived from toxicity studies in laboratory animals and, in our experience, with only a small number of chemicals produc­ing adverse acute effects in the acute toxicity tests (Fig. 1). Thus, if there is to be an in vitro alternative to studies in laboratory animals that will have a role in international labeling and classification, it must be very well validated against the animal model. This difficulty should not, however, preclude the use of in vitro tests per se, although it will certainly have a modifying influence on the rate at which they gain acceptance by regulatory authorities.

a

SYSTEMIC - oral (10%)

                       - dermal (8%)

IRRITATION - skin (20%)

                           - eye (21%)

SENSITISATION - skin (31%)


22%

3%

eye(30%)

skin(40%)

(2%)

(11%)

(8%)

(6%)

c

b

(75%)

                                       

FIGURE 1 Acute toxicity studies (outcome of ICI experiments, 1976-1983). (a) Proportion of studies, (b) Proportion of studies with effects, (c) Proportion of all studies.

The chemical industry is most concerned for the health and safety of people who may be affected by its products and activities. The toxicologist is pivotal in producing the data that can help reduce risks by improving the knowledge and understanding of the hazardous properties of chemical substances. The use of laboratory animals to investigate these hazards is unavoidable until such time as in vitro alternatives have proven ability to predict the dangers to humans.

LITERATURE

1. Jackson S.J., Rhodes C., Oliver G.J.A. Humane approaches to Acute Toxicity Assessment of Industrial Chemicals. // Toxic Substances Journal. 1989. pp.279-299.

2. O Flanerty E.J. Dose Dependens Toxicity. // Commenis Toxicology. 1986. Vol.1. pp. 23-34.

3. Toxicological Evaluations. Potential health hazards of existing chemicals. BG Chemie. Berlin. 1990. 341 p.