Etoposide. Documentation of proposed values of occupational exposure limits (OELs)
Authors: Soćko Renata 
Published: June 2019

Etoposide at room temperature is a solid present in the form of a white or yellow-brown crystalline powder.
It is an anticancer drug with cytotoxic and anti-mitotic activity, used to treat patients with testicular cancer, acute myelogenous leukemia, lung cancer, non-small-cell lung cancer, adrenal cortex cancer, gastric cancer, hepatoblastoma, acute lymphoblastic leukemia and brain tumors. It is also recommended for the treatment of Ewing sarcoma and Kaposi's sarcoma associated with AIDS. This cytostatic is available in capsules taken by food and in concentrate for solution for infusion.
Occupational exposure to etoposide occurs during its manufacture, confectioning, packaging and use in everyday treatment practices of hospital wards.
The monograph, along with the proposal for a hygiene standard for etoposide, was developed as a continuation of work on the determination of the value of hygiene standards for cytostatics. According to the National Consultant's report in the field of nursing in 2010 (incomplete data, covering only 12 voivodeship), the number of nurses employed in oncology facilities totaled 5077.
On the basis of data from the Central Register of Data on Exposure to Carcinogenic or Mutagenic Substances, Mixtures, Agents or Technological Process in Poland exposure to etoposide in Poland in the last three years has been growing. In 2015, 414 people were exposed to the substance.
This substance has not been officially classified in the European Union. Most manufacturers of etoposide importers classify it for carcinogenic activity to category 1.B with risk phrase: May cause cancer and acute toxicity after oral exposure to category 4.
The main effect of the toxicity of etoposide as a medicine is suppression of bone marrow function, which results in neutropenia, granulocytopenia and thrombocytopenia, leukopenia, an increase in the number of megaloblasts in the bone marrow and gastrointestinal symptoms (eg nausea, vomiting with mild to moderate intensity) , bronchospasm, inflammation of mucous membranes, feelings of disgust in the mouth, baldness and secondary leukemia.
According to the IARC, there is limited evidence of carcinogenicity of etoposide in animals, but there is sufficient evidence of carcinogenicity of etoposide in humans when combined exposure to cisplatin and bleomycin.
In IARC, etoposide was classified as probably carcinogenic to humans (Group 2.A.), and in combination with cisplatin and bleomycin as a carcinogen for humans (Group 1).	The genotoxic activity of etoposide has been demonstrated in studies performed on human and animal material in vitro without metabolic activation. Etoposide caused the occurrence of chromosomal aberrations in both humans and experimental animals, increased sister chromatid exchange, double-strand break in DNA and the micronucleus formation.
In experimental animal studies (mice, rats, rabbits), etoposide was teratogenic and embryotoxic. In women treated with etoposide, transient ovarian dysfunction is reported. The effect of etoposide on ovarian function, however, did not depend on the dose, but on the patient's age.
In addition, spontaneous births were reported in women treated with etoposide. In some cases, the embryotoxic effects of the drug have been demonstrated. There were no congenital malformations in children whose mothers were treated with etoposide alone or in combination with other cytostatics, as well as in children of men treated with etoposide.
The critical effect of the action of etoposide as a drug is bone marrow suppression. The lowest therapeutic dose of the drug was found at 2.37 mg/kg/day.
In Poland, the maximum permissible concentrations of etoposide in the work environment have not yet been established.
The following data was taken into account when determining the NDS of etoposide:
- occupational exposure levels established by etoposide manufacturers for this substance amount to 0.0003 or 0.0007 mg/m3;
- available results of human and animal studies do not allow to determine the dose-effect relationship;
- due to the genotoxic, carcinogenic, teratogenic and reproductive effects of etoposide, NIOSH assumed that the OEL should be set at a level below 0.01 mg/m3;
- according to the classification proposed by the group operating within the framework of the "Global strategy of risk management", etoposide should be in category 4, ie substances for which the OEL value in the work environment should be in the range of 0.001 mg/m3 ÷ 0.01 mg/m3.
The MAC value of etoposide was proposed at the level of the equivalent concentration to 0.1% of the lowest therapeutic dose used in humans (2.37 mg/kg), similar to other cytostatics (eg N-hydroxyurea, fluorouracil). An additional uncertainty factor "F" was adopted at level 10 related to the long-term effects of exposure, i.e. genotoxic, carcinogenic and reprotoxic effects of the substance. The MAC of the inhalable fraction of etoposide was set at 0.0017 mg/m3. There are no substantive basis to establish the value of the short- -term (STEL) and permissible concentrations in biological material (DSB) for etoposide.
Based on quantitative data characterizing skin absorption of etoposide, which has a molecular weight of 588.56 and its poor solubility in water, it has been found that the substance is characterized by a low ability to penetrate the skin. Due to the observed embryotoxicity in humans and teratogenic and embryotoxic etoposide in experimental animals, the substance was marked with the letters "Ft" - a substance harmful for reproduction. In addition, the labeling recommended by the manufacturers of "Carc 1.B" that indicated that it is a carcinogenic substance of category 1.B.