Criteria for assessment of occupational exposure to dangerous  pharmaceutical substances Magdalena Galwas, Małgorzata Pośniak   Cloromethane. Documentation Edyta Reszka, Wojciech Wąsowicz Cyanamide. Documentation   Jadwiga Palus, Wojciech Wąsowicz Desflurane. Documentation   Marek Jakubowski   Isoflurane. Documentation Renata Soćko, Małgorzata Kupczewska-Dobecka 4-Methoxyfenol. Documentation   Andrzej Sapota, Małgorzata Skrzypińska-Gawrysiak Nicotine. Documentation Jadwiga A. Szymańska, Barbara Frydrych, Elżbieta Bruchajzer

Criteria for assessment of occupational exposure to dangerous  pharmaceutical substances
Magdalena Galwas, Małgorzata Pośniak

Workers in the pharmaceutical industry are exposed to active substances designed to produce therapeutic effects. Even so, occupational exposure to pharmaceutical substances can be associated with a risk of an adverse health effect. The main problem is the absence of adequate exposure control limits and methods of measuring assessment of dermal and inhalation hazards caused by pharmaceutical ingredients.
This article provides a review of the classification criteria for exposure assessment related to an analysis of toxicological data and to existing classifications of active pharmaceuticals proposed by NIOSH, IACP and IPCS. The recommendations for minimizing or eliminating occupational exposure to pharmaceutical substances are presented.

Cloromethane. Documentation
Edyta Reszka, Wojciech Wąsowicz

Chloromethane, also called methyl chloride, is a colorless, extremely flammable gas, which occurs in chemical plants and naturally in the environment. Methyl chloride is used mainly in the production of silicones. Other sources of exposure to chloromethane include cigarette smoke and burning of waste products. Chloromethane can be absorbed through the respiratory tract and the skin. No information is available regarding its allergenic and irritant effects.
Long-term animal studies have shown that methyl chloride can damage the liver, kidneys, the spleen and the central nervous system. Inhalation studies have demonstrated that chloromethane causes reproductive effects in male rats, including testicular lesions and decreased sperm production. Fetotoxic effects on mice embryos have been observed.
Shortterm exposure to high concentrations of methyl chloride in humans has caused severe neurological effects. Epidemiological human cancer data are limited.
On the basis of a mouse chronic study and short-term human study, the TLV (MAC) value was kept at 20 mg/m³. The Expert Goup also suggested additional notations: “F” (fetotoxic subsatnce), “Sk” (substance absorbed through the skin).

Cyanamide. Documentation
Jadwiga Palus, Wojciech Wąsowicz  

Cyanamide is a combustible, solid substance; it is used as a raw material in the production of pesticides, detergents and some medicines such as antihistamines, antihypertensives, sedatives, contraceptives and also in the treatment of alcoholics. It is also used in the photography industry and as an additive for fuels and lubricants, a paper preservative and as a cement additive. In Europe it is used as a fertilizer, weed killer and defoliant. Occupational exposure to cyanamide occurs mainly during its production and processing in chemical factories and in agriculture when using fertilizers.
Cyanamide strongly irritates the mucous membrane of the eye, the respiratory tract, the digestive tract. It is absorbed through the skin. Cyanamide is hepatotoxic as determined by oral ingestion. Exposure to cyanamide can damage the genetic material, so it may be a mutagenic substance for human and lead to an impairment of the reproductive function in human.
The proposed maximum exposure limit (MAC) for cyanamide in the air (0.9 mg/m3) is based on the value of NOAEL (2 mg/kg/day) derived from long-term oral administration (6 months) studies on rats. This value is in step with that determined in the EU Directive 2006/15/EU. This level of MAC for cyanamide prevents liver damage, and its effects on the central nervous system (headache, fatigue), and the digestive system (nausea, vomiting, diarrhea) induced by cyanamide in alcoholics during detox treatment.
Considering its irritative effects on the eyes and the respiratory system, the Expert Group for Chemical Agents recommended the value of MAC-STEL of 1.8 mg/m3. The skin notation (“Sk”) is recommended.

Desflurane. Documentation  
Marek Jakubowski  

Desflurane is a volatile anesthetic agent, methylethyl ether halogenated solely with fluorine. At room temperature, desflurane is a clear, colorless, volatile nonflammable liquid with an ether-like odor. Exposure levels for medical personnel depend on the method of administering the anesthetic. During endotracheal anesthesia with local exhaust measured levels have been in the 0.2 ÷ 3.0 mg/m³ range. Higher concentrations, up to 36 mg/m3 occurred during intensive therapy or in postoperative rooms.
The anesthetic potency of an inhalation agent is usually expressed in terms of its minimum alveolar concentra-tion (MAC), a steady state concentration that prevents movement of 50% of the subjects in response to a painful stimulus. The MAC of desflurane decreases with age from 9.16% in neonates, 8.3 % in one-year-old children to about 6% in adults. 1 MAC corresponds to the concentration of desflurane of about 85 000 mg/m³. Desflurane is irritating to the airway at concentrations higher than 1 MAC. There is no evidence of renal toxicity or hepatotoxicity with desflurane. Only 0.02 ÷ 0.2% of the dose is metabolized to the potentially toxic metabolites (fluorides, trifluoroacetic acid). Desflurane has a blood gas partition coefficient of 0.42, the lowest of all the available volatile agents, which means that equilibration and recovery occur quickly.
No occupational standard for desflurane is currently defined. Standards recommended by the European health authorities for other volatile anesthetics from this group (enflurane, isoflurane) are from 2 to about 380 mg/m³. In contrast, NIOSH of the USA recommends a general exposure limit of 2 ppm (from 13.8 mg/m³ for desflurane to 16.4 mg/m³ for sevoflurane) for all volatile anesthetics, which is mostly interpreted as a ceiling value.
Like other anesthetics desflurane affects the central nervous system. Assuming the same mechanism of action for all volatile anesthetics, an occupational exposure limit (OEL) of 125 mg/m³ has been calculated for disflurane on the basis of results of a study in which human volunteers were exposed to halothane, enflurane and nitrous oxide, and the MAC vaues of these compounds.

Isoflurane. Documentation  
Renata Soćko, Małgorzata Kupczewska-Dobecka  

Isoflurane is polyfluorinated anaesthetic used during surgical treatment in adult and child patients. It is usually applied as a mixture with oxygen or dinitrogen monoxide. An assessment of health risk from exposure to this inhalant anaesthetic poses a serious problem for employers, mostly due to the fact that this compound belongs to the category for which no Maximum Admissible Concentration (MAC) has been established. Consequently, there is no obligation to measure its air concentration in the workplace. However, the employer is responsible for de-termining whether or not a given hazardous agent is present in the working environment.
The setting of a MAC value for isoflurane has recently been the objective of the activity of the Expert Group for Chemical Agents that has proposed accepting the MAC values of 32 mg/m³ (= 4 ppm) for isoflurane in assessment of workplace hazards. This exposure level is to protect surgical staff from adverse neurological, cardiovas-cular, respiratory and irritant effects.

4-Methoxyfenol. Documentation  
Andrzej Sapota, Małgorzata Skrzypińska-Gawrysiak  

4-Methoxyfenol (4-MF) is a white substance that occurs in the form of crystalline flakes or in the consistency of wax. It has a variety of applications in several industries. Due to its antioxidative properties it is used against peroxidation of fats, oils, vitamins and cosmetics. It is also used as an inhibitor of acrylic and metaacrylic monomer polymerization and various vinyl polymers; as an agent stabilizing chlorinated hydrocarbons, ethyl cellulose, lubricating oil in the textile industry; as an inhibitor of UV radiation effects on the skin and as a skin depigmenting agent; as a chemical intermediate in the production of dyes, pharmaceutics, softening and stabilizing agents; as a drug decolorizing skin residual pigmentation in the case of  vitiligo universalis; and in the treat-ment of melanoma in the skin.
Patients who received a high dose (27 g) of 4-MF in intra-arterial infusion showed symptoms of liver and kidney damage as well as a decreased concentration of hemoglobin.
In the available literature, reports on occupational exposure to 4-MF are rather scarce.

Nicotine. Documentation  
Jadwiga A. Szymańska, Barbara Frydrych, Elżbieta Bruchajzer

Nicotine is an oily, colourless and odourless liquid obtained from leaves of tobacco plants. The most widespread use of nicotine is in tobacco as well as in remedies for nicotine abuse. Nicotine is a component of certain pesticides. Occupational exposure to nicotine is possible during its production and the tobacco drying process. To date only 8 people have been exposed in Poland to nicotine concentration in the air exceeding the TWA value which is 0.5 mg/m³ (data from 2002).
Deadly occupational nicotine intoxication is very rare. The symptoms of severe nicotine intoxication with its small doses are: increased breath stimulation, nausea, vomitting, headache and vertigo, diarrhea, tachycardia, high blood pressure as well as sweating and excessive saliva production. After the administration of high doses of nicotine the following symptoms occured: burning sensations in the oral cavity, throat and stomach, fatigue, palpitations, weakening of the respiratory functions, disturbances of cardiac rhythm, dizziness, weakness, lack of coordination and coma. Death can then occur within 5 minutes up to 4 hours.
Chronic nicotine intoxication leads to disturbances in the circulatory system. Vascular changes may lead to angina pectoris and heart attacks; they also cause: a weakening of memory, a slowdown of physical processes and thought coordination, lack of energy and exhaustion. Disturbances in the digestive system may also occur. Nicotine causes both physical and mental abuse. No epidemiological data was found concerning occupational exposure to nicotine in pure form.
Nicotine is a substance of high acute toxicity to animals. After intragastrical administration the LD50 value is between 3.34 ÷ 188 mg/kg of body weight.
Information concerning toxicity of nicotine indicates its multidirectional influence. Exposure of rats at oral doses (1 mg/kg/day, 9 days or 1.14 mg/kg/day, 34 weeks) caused no changes. When fourfold higher doses were administered to rats, after 34 weeks they caused an increase in the activity of certain enzymes in the heart, and the EEG changed after 9 days. Exposure to nicotine for 28 and 90 days (the accumulated dose was 350 or 315 mg/kg respectively) caused a disturbances in lipid and carbohydrate metabolism.
Nicotine has no mutagenic potential, yet it is genotoxic (sister chromatid exchanges and chromosomal aberrations) as well as fetotoxic.
Nitrosoamines (compounds produced due to tobacco smoking) have proved to show carcinogenic potential.
Nicotine is well absorbed via respiratory tracts, the alimentary canal and the skin. The highest concentrations were detected in the brain, kidneys, stomach mucosa, adrenal medulla, nasal mucosa and salivary glands. Nicotine binds with plasma proteins in 5  20%. It penetrates through placenta and gets to the milk of nursing mothers. During metabolism nicotine can undergo: C-oxidation, demethylation with z C-oxidation, N-oxidation and N-methylation. Nicotine’s core metabolites are: cotinine and nicotine-1’-N-oxide. Nicotine and its metabolites are rapidly discharged by the kidneys.
Smoking cigarettes is the most common example of nicotine activity together with many other compounds. In addition to nicotine, they include hundreds of other substances. Rats simultaneously exposured to ethanol and nicotine have shown impaired fertility and disturbance of immunological reactions occured in the offspring. Nicotine increases the hepatotoxic activeness of CCl4.
Basing on the literature data 1.14 mg/kg/day has been accepted as a NOAEL value of nicotine (no negative results have been observed) whereas 4.56 mg/kg/day has been taken as its LOAEL value.
After an analysis of published data and after conducting necessary calculations the MAC of nicotine in Poland remains unchanged: 0.5 mg/m³ with ‘Sk’ and ‘Ft’ compound symbols.