Etoposide. Documentation of proposed values of occupational exposure limits (OELs)

2019 ◽  
Vol 36 (2(100)) ◽  
pp. 73-98
Author(s):  
Renata Soćko
Keyword(s):  
Lung Cancer ◽  
Bone Marrow ◽  
Occupational Exposure ◽  
Work Environment ◽  
Therapeutic Dose ◽  
Animal Studies ◽  
Myelogenous Leukemia ◽  
Dose Effect ◽  
Sufficient Evidence ◽  
Experimental Animals

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.

scholarly journals On the Nature of Evidence and ‘Proving’ Causality: Smoking and Lung Cancer vs. Sun Exposure, Vitamin D and Multiple Sclerosis

2018 ◽  
Vol 15 (8) ◽  
pp. 1726 ◽  
Author(s):  
Robyn Lucas ◽  
Rachael Rodney Harris
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Lung Cancer ◽  
Vitamin D ◽  
Observational Studies ◽  
Animal Studies ◽  
Disease Risk ◽  
Sun Exposure ◽  
Sufficient Evidence

If environmental exposures are shown to cause an adverse health outcome, reducing exposure should reduce the disease risk. Links between exposures and outcomes are typically based on ‘associations’ derived from observational studies, and causality may not be clear. Randomized controlled trials to ‘prove’ causality are often not feasible or ethical. Here the history of evidence that tobacco smoking causes lung cancer—from observational studies—is compared to that of low sun exposure and/or low vitamin D status as causal risk factors for the autoimmune disease, multiple sclerosis (MS). Evidence derives from in vitro and animal studies, as well as ecological, case-control and cohort studies, in order of increasing strength. For smoking and lung cancer, the associations are strong, consistent, and biologically plausible—the evidence is coherent or ‘in harmony’. For low sun exposure/vitamin D as risk factors for MS, the evidence is weaker, with smaller effect sizes, but coherent across a range of sources of evidence, and biologically plausible. The association is less direct—smoking is directly toxic and carcinogenic to the lung, but sun exposure/vitamin D modulate the immune system, which in turn may reduce the risk of immune attack on self-proteins in the central nervous system. Opinion about whether there is sufficient evidence to conclude that low sun exposure/vitamin D increase the risk of multiple sclerosis, is divided. General public health advice to receive sufficient sun exposure to avoid vitamin D deficiency (<50 nmol/L) should also ensure any benefits for multiple sclerosis, but must be tempered against the risk of skin cancers.

scholarly journals Lung cancer related to occupational exposure: an integrative review

2020 ◽  
Vol 41 ◽  
Author(s):  
Christiane Brey ◽  
Fernanda Thaysa Gouveia ◽  
Brenda Silva Silva ◽  
Leila Maria Mansano Sarquis ◽  
Fernanda Moura D’Almeida Miranda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Occupational Exposure ◽  
Work Environment ◽  
Analytical Study ◽  
Lung Cancer Risk ◽  
Scientific Evidence ◽  
Secondary Sector ◽  
Exposed Workers ◽  
Carcinogenic Agents ◽  
Carcinogenic Substances

ABSTRACT Objective: To identify in the literature the carcinogenic agents found in the work environment, the occupations and the risk for lung cancer. Method: A descriptive and analytical study of the Integrative Literature Review type was carried out in national and international databases from the last ten years in the period from 2009 to 2018, concerning 32 studies referring to association between carcinogenic substances to which the worker is exposed and lung cancer. Results: Nine (28.1%) publications originated in China and only one in Brazil. The most exposed workers were from the secondary sector, 50% being from industry and 6.2% from construction, mostly male. Asbestos and silica stood out among the carcinogenic substances most associated with lung cancer risk, accounting for 37.5% and 28.1%, respectively. Conclusions: The association between occupational exposure and the risk for lung cancer was characterized in this research by the substantial scientific evidence from the described studies that confirm this association.

Phenylhydrazine and its salts – calculated on phenylhydrazine. Documentation of proposed values of occupational exposure limits (OELs)

2018 ◽  
Vol 34 (4(98)) ◽  
pp. 113-148
Author(s):  
Anna Kilanowicz ◽  
Małgorzata Skrzypińska-Gawrysiak
Keyword(s):  
Lung Cancer ◽  
Occupational Exposure ◽  
Blood Vessels ◽  
Oral Route ◽  
Lung Tumors ◽  
Dose Effect ◽  
International Agency ◽  
Carcinogenic Activity ◽  
Heinz Bodies ◽  
Phenylhydrazine Hydrochloride

Phenylhydrazine at room temperature is a colorless or yellow oily liquid, at lower temperatures it occurs in a form of a crystalline Phenylhydrazine is used in an organic synthesis as a powerful reducing agent or as an intermediate in synthesis of other chemical compounds, such as dyes and drugs. Phenylhydrazine is also used as a chemical reagent. At the beginning of the 20th century, phenylhydrazine was used as a drug in polycythemia vera and other blood disorders. Occupational exposure to phenylhydrazine and its salts may occur during the production, further processing and distribution of these compounds, and also during their use. In 2014, 711 people were exposed to phenylhydrazine in Poland (including 531 women), of which 2 people only were exposed to phenylhydrazine in the air at a concentration range> 0.1–0.5 of the MAC value (20 mg/m3) . Phenylhydrazine is classified as a toxic substance after oral administration, in contact with skin and after inhalation. The available literature describes several cases of human poisoning with phenylhydrazine with inhalation and through the skin. Adverse effects of phenylhydrazine exposure are progressive hemolytic anemia with hyperbilirubinaemia and urobilinemia, presence of Heinz bodies in red blood cells, impairment of renal and hepatic function as secondary symptom to the haemolytic activity of phenylhydrazine. Methemoglobinemia and leukocytosis sometimes occurred. General symptoms of poisoning included dizziness, diarrhea, general weakness and reduced blood pressure. Phenylhydrazine irritates the skin. Several cases of skin hypersensitivity reactions to phenylhydrazine and its hydrochloride have also been described. It has been shown that phenylhydrazine gives cross-reactions with hydrazine salts. In animals, the main symptoms of acute phenylhydrazine poisoning were the formation of significant amounts of methaemoglobin and its consequences: hemolysis, Heinz bodies formation, reticulocytosis, bone marrow hyperplasia, splenomegaly and liver damage. Motor excitation and tonic-clonic spasms were also observed. As a result of repeated exposure, it was found that phenylhydrazine also causes hemostatic disorders in addition to haemolytic anemia and leads to acute pulmonary thrombosis. The dose-effect relationship cannot be derived from existing data nor the NOAEL value be determined. Phenylhydrazine is an in vitro mutagen and some evidence points to its genotoxic activity in vivo (DNA methylation and fragmentation ). Phenylhydrazine and its salts have been classified as category 2 mutagenic substances. In the available literature and databases, no information was found on the carcinogenic activity of phenylhydrazine and its salts in humans. Carcinogenic activity of phenylhydrazine has been demonstrated in experimental animals. Exposure of mice via oral route resulted in the occurrence of lung tumors and tumors of blood vessels. The International Agency for Research on Cancer (IARC) does not classify phenylhydrazine and its salts as carcinogenic. In the European Union, phenylhydrazine and its salts have been classified as category 1B carcinogens. There is also insufficient data on the effect of phenylhydrazine on reproduction and developmental toxicity, so it is difficult to assess whether these effects may occur in humans exposed to phenylhydrazine and its salts. Based on the observed systemic effects in humans and animals exposed to phenylhydrazine and its salts, it can be assumed that these compounds are absorbed into the body by inhalation, oral route, through the skin and after parenteral administration. There are no quantitative data on the absorption efficiency of individual routes. The main metabolic pathways of phenylhydrazine are hydroxylation to p-hydroxyphenylhydrazine and formation of phenylhydrazones by reaction with natural keto-acids. Metabolites in the form of glucuronides are mainly excreted in the urine. The existing two studies of the carcinogenic activity of phenylhydrazine hydrochloride have shown that the compound administered via the oral route caused a significant increase in the formation of lung tumors or tumors of blood vessels. In the second study, despite the longer exposure time, no significant increase in lung cancer was observed. Although the results of both studies seem to be unreliable in the light of current criteria and are limited to one species (mice) only and one dose, on the basis of them, phenylhydrazine was classified in the EU as a carcinogen category 1B with the assigned phrase H350 - may cause cancer. A quantitative evaluation of phenylhydrazine carcinogenicity was performed using data on the incidence of lung cancer in mice of both genders exposed to phenylhydrazine hydrochloride, administered intragastrically at 1 mg/day. The model adopted for calculations shows that exposure to phenylhydrazine, at the level of the adopted MAC value in Poland (20 mg/m3) over 40 years of work, corresponds to the risk of lung cancer at the level of 5.7 · 10-2. Such risk is unacceptable. From the estimation of cancer risk, it appears that the current value of MAC for substance should be reduced. The existing database on the toxicity of phenylhydrazine and its salts is insufficient to derive a MAC value based on NOAEL/LOAEL values. Due to the mechanism of action and the main toxic effects (haematotoxicity), phenylhydrazine has an aniline-like toxicological profile. It was proposed that the MAC value for phenylhydrazine should be taken analogously to the MAC value for aniline, i.e. 1.9 mg/m3, which corresponds to the risk of lung cancer in occupational exposure conditions of 5.4 · 10-3. Due to the dermal absorption of phenylhydrazine, the "skin" notation has been proposed (absorption through the skin may be as important as in the case of inhalation). Additionally, due to irritating, sensitizing, carcinogenic and mutagenic effects of phenylhydrazine, the normative should be marked with the letters "I" (substance with an irritating effect), "A" (a substance with sensitizing effect), Carc. 1B (carcinogenic substance category 1B) and Muta. 2 (mutagen category 2). There are no evidence to establish the STEL and BEI values.

scholarly journals On the nature of evidence and 'proving' causality: smoking and lung cancer vs. sun exposure, vitamin D and multiple sclerosis

2018 ◽  
Author(s):  
Robyn Lucas ◽  
Rachael Rodney Harris
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Lung Cancer ◽  
Vitamin D ◽  
Observational Studies ◽  
Animal Studies ◽  
Disease Risk ◽  
Sun Exposure ◽  
Sufficient Evidence

If environmental exposures are shown to cause an adverse health outcome, reducing exposure should reduce the disease risk. Links between exposures and outcomes are typically based on ‘associations’ derived from observational studies, and causality may not be clear. Randomised controlled trials to ‘prove’ causality are often not feasible or ethical. Here the history of evidence that tobacco smoking causes lung cancer – in observational studies – is compared to that of low sun exposure and/or low vitamin D status as causal risk factors for the autoimmune disease, multiple sclerosis. Evidence derives from in vitro and animal studies, as well as ecological, case-control and cohort studies, in order of increasing strength. For smoking and lung cancer, the associations are strong, consistent, and biologically plausible – the evidence is coherent or ‘in harmony’. For low sun exposure/vitamin D as risk factors for MS, the evidence is weaker, with smaller effect sizes, but coherent across a range of sources of evidence, and biologically plausible. The association is less direct – smoking is directly toxic and carcinogenic to the lung, but sun exposure/vitamin D modulate the immune system, which in turn may reduce the risk of immune attack on self-proteins in the central nervous system. Opinion about whether there is sufficient evidence to conclude that low sun exposure/vitamin D increase the risk of multiple sclerosis, is divided. General public health advice to receive sufficient sun exposure to avoid vitamin D deficiency (&lt;50nmol/L) should also ensure any benefits for multiple sclerosis.

EFFECT OF KAGOCEL PREPARATION ON THE GENERATIVE FUNCTION OF EXPERIMENTAL ANIMALS AT ITS ADMINISTRATION IN THE INFANTILE PERIOD OF THEIR DEVELOPMENT

2017 ◽  
pp. 42-49
Author(s):  
T. A. Borovskaya ◽  
M. E. Poluektova ◽  
A. V. Vychuzhanina ◽  
V. A. Mashanova ◽  
Yu. A. Shchemerova
Keyword(s):  
Toxic Effect ◽  
Reproductive System ◽  
Safety Profile ◽  
Therapeutic Dose ◽  
Antiviral Drug ◽  
Experimental Studies ◽  
Reproductive Age ◽  
Pathological Changes ◽  
Pediatric Practice ◽  
Experimental Animals

In experimental studies on rats (males, females) at their infantile stage starting from 10 days, a potential delayed toxic effect of the antiviral drug Kagocel on the reproductive system was studied. The drug was administered for 12 days in a therapeutic dose and at a dose 10-fold higher than the therapeutic one. Reproductive safety was estimated after animals reached the reproductive age (2.5 months). It was found out that the drug, when administered in both doses, does not decrease the fertility of animals, does not induce morphological and pathological changes in the sex glands, and does not have toxic effect on the offspring. Obtained data characterize Kagocel as a preparation with a wide reproductive safety profile and show that it can be used in pediatric practice for infants.

154 Marrow-infiltrating lymphocytes (MILs): A novel adoptive immunotherapy for hematological and solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A168-A168
Author(s):  
Eric Lutz ◽  
Lakshmi Rudraraju ◽  
Elizabeth DeOliveira ◽  
Amanda Seiz ◽  
Monil Shah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Memory T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Blood Samples ◽  
Infiltrating Lymphocytes

BackgroundMarrow infiltrating lymphocytes (MILsTM) are the product of activating and expanding bone marrow T cells.1 The bone marrow is a specialized niche in the immune system enriched for antigen-experienced, memory T cells. In patients with multiple myeloma and other hematological malignancies that relapse post-transplant, MILs have been shown to contain tumor antigen-specific T cells and adoptive cell therapy (ACT) using MILs has demonstrated antitumor activity.2 3 The bone marrow has been shown to harbor tumor-antigen specific T cells in patients with melanoma,4 5 glioblastoma,6 breast,7 non-small-cell lung8 and pancreatic cancers.9 Here, we sought to determine if tumor-specific MILs could be expanded from the bone marrow of patients with a range of different solid tumors.MethodsBone marrow and blood samples were collected from patients with advanced and metastatic cancers. To date, samples have been collected from a minimum of four patients with non-small cell lung cancer (NSCLC), prostate cancer, head and neck cancer, glioblastoma, and breast cancer. Samples from patients with multiple myeloma were used as a reference control. Utilizing a 10-day proprietary process, MILs and peripheral blood lymphocytes (PBLs) were activated and expanded from patient bone marrow and blood samples, respectively. T cell lineage-specific markers (CD3, CD4 and CD8) were characterized by flow cytometry pre- and post-expansion.Tumor-specific T cells were quantitated in expanded MILs and PBLs using a previously described cytokine-secretion assay [2]. Briefly, autologous antigen-presenting cells (APCs) were pulsed with lysates from allogeneic cancer cell lines and co-cultured with activated MILs or PBLs. APCs pulsed with irrelevant mis-matched cancer cell line lysates or media alone were used as negative controls. Tumor-specific T cells were defined as the IFNgamma-producing population by flow cytometry.ResultsMILs were successfully expanded from all patient bone marrow samples tested, regardless of tumor type. Cytokine-producing tumor-specific CD4+ and CD8+ T cells were detected in each of the expanded MILs. In contrast, tumor-specific T cells were not detected in any of the matched activated and expanded PBLs.ConclusionsMILs have been successfully grown for all solid tumor types evaluated, including NSCLC, prostate, head and neck, glioblastoma and breast cancer. Clinical studies have been completed in patients with multiple myeloma and other hematological cancers. 2 3 A phase IIa trial to evaluate MILs in combination with a checkpoint inhibitor is underway in patients with anti-PD1/PDL1-refractory NSCLC (ClinicalTrials.gov Identifier: NCT04069936). The preclinical data presented herein demonstrate that expanding MILs is feasible. MILs-based therapies hold therapeutic promise across a wide range of tumor indications.Ethics ApprovalThis study was approved by each participating instituion’s IRB.ReferencesBorrello I and Noonan KA. Marrow-Infiltrating Lymphocytes - Role in Biology and Cancer Therapy. Front Immunol 2016 March 30; 7(112)Noonan KA, Huff CA, Davis J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci. Transl. Med 2015;7:288ra78.Biavati L, Noonan K, Luznik L, Borrello I. Activated allogeneic donor-derived marrow-infiltrating lymphocytes display measurable in vitro antitumor activity. J Immunother 2019 Apr;42(3):73–80.Müller-Berghaus J, Ehlert K, Ugurel S, et al. Melanoma-reactive T cells in the bone marrow of melanoma patients: association with disease stage and disease duration. Cancer Res 2006;66(12):5997–6001.Letsch A, Keilholz U, Assfalg G, et al., Bone marrow contains melanoma-reactive CD8+ effector T Cells and, compared with peripheral blood, enriched numbers of melanoma-reactive CD8+ memory T cells. Cancer Res 2003 Sep 1;63(17):5582–5586.Chongsathidkiet P, Jackson C, Koyama S, et al., Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nature Medicine 2018 Aug 13; 24:1459–1468.Feuerer M, Rocha M, Bai L, et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int J Cancer 2001; 92(1):96–105.Safi S, Yamauchi Y, Stamova S, et al. Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer. Oncoimmunology 2019;8(12):e1671762.Schmitz-Winnenthal FH, Volk C, Z’Graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005;65(21):10079–87.

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