Toluene exposure and changes in platelet count: a narrative review

Toluene is a widely used solvent whose many toxic effects include neurological and hematological damage. This study reviewed evidence about the effects of toluene exposure on platelet count in humans. Three electronic databases and a digital library of theses and dissertations were searched using a specific strategy, yielding 64 articles, of which 14 were selected. These studies assessed a total of 15,759 participants, including 13,297 exposed individuals, mainly women exposed in an environmental setting. The major findings were: (1) conflicting results (positive, inverse, or no association), (2) cross-contamination with other substances, which impaired assessment of the relationship, and (3) a lack of studies. Thus, further research is needed on this topic, especially toluene exposure in isolation from associated substances.


INTRODUCTION
Solvents are widely used chemical substances that dissolve solutes.][3] Toluene is in a group of solvents called aromatic hydrocarbons. 1It can be found naturally or can be artificially synthesized.In nature, it occurs in crude oil and balsam of Tolu, a South American tree. 4It is used in the processing of fossil fuels and the production of cleaning products, glues, paints, and cosmetics. 1It is also among the most widely abused inhaled recreational drugs, 5,6 despite knowledge of its many toxic effects.
Inhalation is the primary route of exposure, and the compound is rapidly absorbed by the lungs.It is then distributed through the bloodstream, preferentially to fat, brain, bone marrow, liver, and kidney tissue. 4ignificant amounts can also be absorbed through ingestion and dermal contact, although at a slower rate. 4,5Toluene is metabolized into benzoic acid in the liver and, after conjugation with glycine, forms hippuric acid, which is excreted through urine, the main route of elimination.
Toluene has many toxic effects, although the mechanism by which it produces systemic toxicity has not been yet established. 7The central nervous system is the primary target of acute and chronic exposure. 6t also has toxic effects on the respiratory system (eg, chemical pneumonitis), liver (eg, hepatitis), and kidneys (eg, tubular necrosis). 1All of these effects depend on the concentration, length of exposure, and individual susceptibility. 80][11][12][13][14][15] Immune thrombocytopenic purpura (ITP), a rare hematological disorder characterized by thrombocytopenia (reduced platelet count [PC]), has also been reported after toluene exposure. 10,11is study aims to review evidence in the literature about human toluene exposure and PC changes.

METHODS
This narrative review collected data about the effects of toluene on PC.In January 2021, we developed a search strategy for 3 electronic databases (BVS/LILACS; Embase and MEDLINE/PubMed) and the Fiocruz ARCA Digital Library of Theses and Dissertations using the following search terms: toluene, thrombocytopenia, thrombocytopenic, platelet, count, hematologic, parameter and measure.To these were added the Boolean operators ("AND", "OR" and "NOT"), and MeSH and DeCS equivalents.The reference lists of the selected articles were also manually reviewed.Articles already indexed by MEDLINE were excluded from the search in BVS/LILACS and Embase to avoid duplicates.
The selection criteria were observational studies, clinical trials, systematic reviews, dissertations, and theses on human exposure to toluene that also included PC, thrombocytopenia, or thrombocytopenic purpura.Only studies published between 1950 and 2021 in English, Spanish, or Portuguese were eligible.We did not include animal or in vitro studies, editorials, expert opinions, narrative reviews, or book chapters.We divided the participants into 3 age groups: children and teenagers (aged ≤17 years), adults (aged 18-64 years), and older adults (aged ≥60 years). 16,17

RESULTS
The main search was performed on January 28, 2021, yielding 64 records, 1 from BVS/LILACS, 18 from Embase, 45 from MEDLINE, and 0 from Fiocruz/ ARCA.After 1 duplicate was removed, 30 records were selected based on title and abstract screening.After full-text analysis, 11 were selected.Three additional articles were included from a reference list search, for a total of 14 articles.The 51 exclusions were due to unrelated themes (40), publication in other languages (7), or animal studies (5). Figure 1 shows the study selection flowchart.
All included studies were observational: 7 were cross-sectional, 4 were case reports, and 3 were cohort studies.They were published between 1963 and 2020, with the majority (85%) published in the last decade.The articles originated from 9 countries: 4 from the United States, 2 each from Nigeria and South Korea, and 1 each from Canada, China, Iran, Mexico, Taiwan, and the United Kingdom.

DISCUSSION
In the literature, toluene exposure has been associated with hematological effects in humans, including reduced red blood cell count, hemoglobin concentration, increased white blood cell count, decreased and increased PC, and ITP. 9,11,14,22o conclusions could be drawn about the effects of toluene on PC based on the included studies, with some finding increases, decreases, or no effect.However, some confounders should be pointed out.The increased PC reported in some studies may be a consequence of a particular type of anemia, such as iron deficiency anemia, a recognized cause of reactive thrombocytosis, which may be due to increased megakaryopoiesis stimulated by such deficiency. 27dditionally, PCs were higher among smokers.One possible explanation for this may be that 1 or more chemical constituents of cigarette smoke stimulate bone marrow to increase production of certain blood components, such as white cells and platelets.The fact that young male smokers have higher white blood cell and PCs and lower hematocrit levels than nonsmokers is consistent with the hypothesis that inhalation of cigarette smoke causes inflammatory reactions, although studies have found that adult smokers have elevated hematocrit levels. 28t has been reported that low-level toluene exposure can lead to transient platelet agglutination, which can result in pseudo-thrombocytopenia.Therefore, in the included studies, the PC reduction in workers with long-term continuous toluene exposure could have been due to transient hyper-agglutination, a platelet synthesis disturbance, or increased platelet damage. 18,29s previously mentioned, 1 case report 10 described exacerbated ITP after toluene exposure without associated substances.This suggests that toluene's relationship with ITP may be aggravation, rather than causation.A different case report 26 described 2 cases of ITP after exposure to toluene diisocyanate.Hence, this specific isoform of toluene may play a role in the development of ITP.
There has been some debate about toluene's hematological effects, mainly due to crosscontamination with other volatile organic compounds, such as BTEX, being benzene a well-established hematotoxic substance. 9,30BTEX chemicals, which are often analyzed together, are thought to share some similar, non-carcinogenic effects. 14As pointed out in the literature, cross-contamination, especially with benzene, is a potential confounder for the overall results of our study. 9,24,304][35][36] Some studies have reported that the interaction between benzene and toluene decreases the hematotoxicity of benzene, 37,38 while another reported that a mixture of toluene and benzene considerably increased the adverse effects of benzene on some hematological components, such as lymphocytes. 39These effects may be related to varying concentrations of benzene and toluene. 21,40][42][43] Most previous studies on the consequences of oil spills have compared an exposed group to an unexposed control group. 25Such studies can help clarify the acute effects of BTEX exposure, since the exposure period can be easily quantified, along with the exact agents.This is in contrast to environmental studies, which include broad populations and provide data on chronically exposed individuals with varying exposure periods.
Most exposed participants were environmentally exposed women, whose exposure was determined through biomarkers in blood samples.This contrasts with the common-sense expectation of men 44 with industrial jobs involving toluene in the production process.The predominance of environmentally exposed participants was due to a small number of studies, 14,22 which heavily skewed the data in that direction.However, we could not specifically account for the higher number of exposed women.
Nevertheless, we were able to shed some light on this understudied theme, collecting relatively comprehensive data that indicate contamination by a mixture of substances.Such cross-contamination could impair assessment of toluene's hematotoxicity in humans.
We must also point out certain study limitations, the first of which is the review design.We tried to mitigate the bias associated with narrative reviews by using a transparent search strategy that included: precise and uniform search terms (MeSH and DeCS) and inclusion and exclusion criteria; a search of several databases, including grey literature; and a manual search of the references of relevant articles to expand the search.Second, due to cross-contamination by other substances, mainly benzene, we could not determine the extent to which PC was affected by toluene in most of the studies.Furthermore, we may have disregarded other unmeasured confounders in the studies.

CONCLUSIONS
Our findings highlight the scant data on toluene exposure and PC changes in the literature, especially exposure to toluene apart from other associated substances.Since the available data are contradictory, no clear conclusions can be drawn.The potential deleterious effects of toluene exposure on PC should be considered.Further research is needed to investigate this relationship, especially studies that include toluene exposure in isolation and the development or exacerbation of ITP through toluene diisocyanate.

Table 1 .
Selected data from the included studies