Investigating the general effects of different types of toluene exposure on the health of workers: an integrative review of the literature

Abstract

Objectives

This integrative review aims to evaluate the available empirical and theoretical literature on the effects caused by different types of occupational toluene exposure on the health of workers. We aim to guide future research, legislation, and guidelines with evidence-based recommendations on toluene exposure.

Design

An integrative review of the literature.

Data sources

A systematic search strategy was undertaken across five electronic databases; PubMed, Scopus, Medline, CINAHL and ScienceDirect. Furthermore, grey literature was incorporated through hand-searching databases, Google Scholar, open-access engines and Google Advanced Search tool, among other tools.

Eligibility criteria

Studies investigating the effects of occupational toluene exposure between 2010 and July 2023 were included. Inclusion criteria included full-text English articles, workers aged 18–65, and studies with co-exposures to benzene, toluene, ethylbenzene and xylene or volatile organic compound if direct findings to toluene were reported. Notable exclusion criteria were non-human studies, pregnant women, paediatric and geriatric populations, and studies addressing toluene abuse and not occupational exposure.

Data extraction and synthesis

27 studies met the eligibility criteria and were appraised using the Mixed Methods Appraisal Tool. Data were systematically extracted, guiding the synthesis of various themes, namely acute exposure effects, chronic exposure effects, short-term effects, long-term effects, low-dose effects, high-dose effects and reversible versus irreversible effects.

Results

The review demonstrated that occupational toluene exposure impacts health differently depending on the nature and context of the exposure. Effects can arise in both acute and chronic scenarios, with outcomes that vary by duration, dose and whether the effects are reversible or irreversible.

Conclusions

The results demonstrate that toluene exposure can cause a wide range of effects based on the type of occupational toluene exposure. These findings can be used to update current guidelines on the recommended threshold limit for toluene exposure. Furthermore, strategies such as implementing mandatory personal protective equipment, improving ventilation and educating workers on the risks of toluene exposure can be put in place to mitigate the risks.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Prior to this review, the characteristic effects of different types of occupational toluene exposure were limited and mainly included acute and chronic effects on the neurological system.

WHAT THIS STUDY ADDS

• This review reveals that occupational toluene exposure induces varied health effects dependent on exposure type and setting. The findings contribute a nuanced understanding of acute and chronic effects, encompassing short-term, long-term, low-dose, high-dose, reversible and irreversible outcomes, providing a previously unavailable comprehensive picture. The review uncovered effects on various systems, including the cardiovascular, neurological and respiratory systems, as well as potential genotoxic and carcinogenic effects.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• The implications of this study extend to research, practice and policy. The identified characteristic effects can inform future research directions, guiding the development of evidence-based recommendations for toluene exposure. Additionally, the findings support the need for updated guidelines, recommending specific threshold limits for toluene exposure. Practical strategies, including mandatory protective measures and enhanced worker education, are advised to mitigate the identified health risks in occupational settings.

Introduction

Toluene is a colourless chemical liquid comprising benzene with a single methyl substituent, which, though naturally present in crude oil, is commonly used in manufacturing settings, such as adhesive, lacquer, paint, polish and rubber industries.¹ Consequently, people involved in the manufacturing of these substances are commonly exposed to toluene.² The Deepwater Horizon Oil Spill of 2010 shed light on the importance of investigating the effects of polycyclic aromatic hydrocarbons, as well as volatile organic compounds (VOCs), such as benzene, toluene, ethylbenzene and xylene (BTEX), since workers who participated in clean-up efforts following the disaster reported a range of signs and symptoms when doing so, highlighting how said compounds had not been thoroughly explored for their effects on human health.³

Exposure to toluene specifically has been a cause for concern, with toluene’s deleterious health effects being well noted in the literature, including detriment to the cardiovascular, respiratory, hepatic, renal, dermal and neurological systems.^{4 5} How toluene can impact these systems, however, can vary with the nature of exposure, and the effects of toluene exposure have diverse characteristics. Toluene’s effects can vary depending on whether one faces acute or chronic exposure to toluene. Furthermore, the effects of toluene exposure can be short-term or long-term in nature. The dosage of toluene that one is exposed to may mediate the impact toluene imposes on one’s health, particularly pertinent to workers, as information on such establishes the basis of guidelines on permissible levels of toluene in the workplace.⁵ The extent of the permanency of toluene’s effects on health can also vary, with some being reversible and others being irreversible.⁶ Ultimately, the health effects of toluene can have striking variations in character.

Toluene’s health harms have been thoroughly researched, with much of this research exploring the effect of occupational exposure to toluene.^{4 5} However, said research has not been synthesised to establish the effects of occupational exposure to toluene. Some published literature reviews do address toluene’s effect on workers when combined with other VOCs; however, the characteristics of toluene’s individual impact on workers, as well as the differentiation of these, have not been the subject of a review, making this review the first of its kind.

This integrative review of the literature (IRL) aimed to evaluate the available empirical literature on the characteristic effects caused by different types of occupational toluene exposure on the health of workers. Based on these findings, we aim to advise on future research, legislation and occupational guidelines. It may also serve as a valuable resource for researchers, health professionals and policymakers, facilitating a better understanding of the potential risks and aiding in developing effective preventive measures and interventions.

Methods

The review followed a modified version of the integrative review framework by Whittemore and Knafl.⁷ The IRL methodology ought to be thoughtfully constructed to maximise a topic’s exploration while maintaining reliability and validity. Subjects are often studied through a range of study designs which the IRL can account for.⁸ The IRL’s holistic nature gives it more utility as a tool to inform future research and policy-making decisions.⁹

Stage 1: Problem identification

The problem identification stage involved investigating the relevant literature for gaps in knowledge for this IRL to address and provide a comprehensive, up-to-date report on the known effects of toluene exposure in the occupational setting, and objectives for the IRL were generated to guide the investigation of the data found to yield an in-depth review of how the known effects of toluene manifest themselves in relation to different variables. The objectives included identifying the effects caused by toluene exposure at acute vs chronic exposure, as well as the short-term and long-term effects, understanding the types of effects caused by toluene exposure at different doses (high vs low), classifying the effects identified as either reversible or irreversible, and finally, providing recommendations based on the findings regarding exposure threshold limits and measures to reduce adverse effects to occupational toluene exposure.

Stage 2: Literature search

A search question was formulated using the PICO (Patient/Population, Intervention, Comparison, Outcomes) framework. The PICO-based formulated question, ‘Effects of Toluene Exposure on the Health of Workers’, was then employed to generate relevant terms and search questions.

The literature search was conducted throughout June and July of 2023 and included a systematic search across PubMed, Medline, CINAHL Ultimate, SCOPUS, Science Direct and the library database at RCSI. Hand-searching databases and websites for relevant literature were conducted mainly through the Google Scholar website and the PubMed electronic database to identify literature not found by databases in the initial search. Grey literature, defining literature in integrative reviews, was also employed, and included searching professional, governmental and international organisations such as the WHO for relevant articles or studies. Furthermore, other open-access search engines were used, such as Summon, Core.ac.uk, also known as the CORE database and the Google Advanced Search tool.

Various combinations with operators were initially employed with a wide range of search terms as displayed in table 1. The search strategies and queries were refined iteratively to enhance specificity until a final combination of search terms was determined. Notably, employing phrases like “Effects of Toluene” instead of isolated terms like “Toluene” AND “Effects” proved to yield more pertinent literature during the searches.

Table 1. Patient/Population, Intervention, Comparison, Outcomes constituent terms and synonyms used to expand the scope of search.

Effects	Toluene	Health	Workers
“Effects”“Side Effects”“Consequences”“Toxicity”“Impact”“Reaction”“Health effects”“Repercussions”“Exposure”“Influence”“Adverse”“Risks”“Adverse Effects”“Hazards”“Short-term effects”“Long-term effects”“Results”“Outcome”“Action”	“Methylbenzene”“Phenylmethane”“Toluene Exposure”“Dracyl”“Toluene effects”	“Health”“Workers Health”“Health effects”	“Healthcare workers”“Workforce”“Industrial Workers”“Manufacturing”“Laborers”“Occupation”“Occupational”“Employees”
Phrases
“Effects of Toluene on the Health of Workers”“The effects of toluene on the health of workers”“Effects of Toluene”“Acute effects of toluene”“Chronic effects of toluene”“Short-term effects of toluene”“Long-term effects of toluene”“Effects of toluene exposure health effects respiratory”“Occupational toluene exposure”“Effects of occupational toluene exposure”“Effects of toluene or methylbenzene on workers’ health”“Effects of toluene on workers”“What are the effects of toluene on the health of workers?”

Table 2 portrays the inclusion and exclusion criteria for screening the search results. Articles had to be related to the main search questions identified or explored during the problem identification stage. Articles were selected for review and initial title and abstract screening if they referred to the health-related effects of toluene in the general population or in a specific population, such as a group of workers, as well as other studies exploring toluene’s characteristics or monitored levels in areas that discussed or revealed any reported health effects.

Table 2. Inclusion and exclusion criteria.

Inclusion	Exclusion
English	Non-English
Year range: 2010–2023	Pre-2010
Working age population: 18–65	Non-working age population (<18 or >65)
Workers only—no vulnerable groups, for example, pregnant women	Non-workers
Only human studies	Non-human studies (animal studies, for example)
Co-exposures, BTEX, VOC studies if direct toluene findings presented	Co-exposures, BTEX, VOC studies not addressing toluene directly
Both genders (males, females)	Studies addressing toluene abuse (not occupational)
Full-text articles	Healthy volunteers (unless occupationally exposed)
All and any publications related to the review questions and the topic addressed by the integrative review: Effects of toluene on the health of workers Short-term and/or long-term effects Acute and/or chronic effects Any reported effects

BTEX, benzene, toluene, ethylbenzene and xylene; VOC, volatile organic compound.

The articles selected were run through rigorous inclusion and exclusion criteria, summarised in table 2. To capture the nature of working populations across most jurisdictions, only human studies on males or females between 18 and 65 years were included. Vulnerable groups such as pregnant women were excluded, and the effects of toluene exposure on fetal development and congenital disabilities were also disregarded to provide a more representative report of the effects on workers from occupational settings. Additionally, in fulfilling the aim of this integrative review, studies on the short-term or long-term and acute or chronic effects of toluene on workers’ health were included. Studies on participants outside of the confines of the occupational setting were excluded to ensure workers remained the focus of this present study.

Based on the search terms and phrases used, along with the employed inclusion and exclusion criteria, the initial search retrieved a total of 2953 records. After removing duplicates, the total number of records identified was 729. These records were subsequently screened for relevance based on the title and abstract, resulting in 208 studies being retained and sought for full-text retrieval. Only one study was not retrieved for its full-text version as it had only been published as an abstract. The remaining 207 articles were assessed for eligibility, and 27 studies met the inclusion and exclusion criteria and were included in the final data extraction and synthesis review. The process of refining and evaluating the records retrieved in the literature search is presented in figure 1.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart displaying stages of article selection.

Stage 3: Data evaluation

The data evaluation stage aimed to ensure that the included studies met the standards for inclusion following critical appraisal of the studies’ designs. The 27 studies included consisted of eight qualitative studies, 16 quantitative non-randomised studies and 3 quantitative descriptive studies. All studies had been assessed and ensured to meet the set inclusion and exclusion criteria before being evaluated and quality appraised.

The Mixed Methods Appraisal Tool (MMAT) was used to evaluate the methodological quality of qualitative, quantitative and mixed methods studies.¹⁰ The MMAT is widely recognised as a broad, reliable and valid instrument for systematic and integrative reviews. MMAT is only used to evaluate empirical non-theoretical research with experiments and observations.¹⁰ Overall, the quality of the included studies was adequate, with an average score of 3.7 (74%) and scores ranging from 2 (40%) to 5 (100%) (table 3). As there are no clear guidelines in the MMAT framework for excluding studies at a specific cut-off score, none were excluded based on their quality due to their relevance to the review’s objectives.

Table 3. MMAT scores of included studies.

Study	MMAT score
Arslan et al 201823	4
Türkoğlu et al, 201012	5
Cassini et al, 201129	4
Shih et al, 201115	2
Al-Batanony et al, 201220	2
Hosni et al, 202017	3
Tunsaringkarn et al, 201131	2
Ahmadi Asour et al, 201627	3
Chaigne et al, 201533	4
Decharat, 202152	3
Tunsaringkarn et al, 201224	3
Maryiantari and Keman, 202026	3
Gupta et al, 201121	5
Van Hooste, 201716	5
Ngajilo and Ehrlich, 201735	5
Ishar et al, 202114	3
Jiménez-Garza et al, 201228	3
Wartono et al, 201537	5
Priya et al, 201530	5
Kobayashi, 201325	4
Tualeka et al, 201934	4
Muttray et al, 201922	4
Zamyslowska-Szmytke et al, 201113	4
Hadkhale et al, 201736	4
Kim et al, 201119	4
Manikantan et al, 201032	3
Oginawati et al, 202118	4

MMAT, Mixed Methods Appraisal Tool.

Stage 4: Data extraction and analysis

Data was extracted and analysed from the collated literature in a standardised fashion and is presented in online supplemental table. The data extraction sheet of the 27 extracted studies guided the synthesis of various themes in the results section that addressed how the known effects of occupational toluene exposure manifested themselves in workers. The synthesised sections included acute exposure effects, chronic exposure effects, short-term effects, long-term effects, low-dose effects, high-dose effects and reversible versus irreversible effects.

Patient and public involvement

Given the nature of this study’s design, it was not appropriate or possible to involve patients or the public in our review’s design, conduct, reporting or dissemination plans. The review did not involve or require any patient or participant recruitment; thus, no patient or public involvement occurred. Despite the absence of direct patient or public engagement, it is essential to note that the development of our research question was informed by careful consideration of the significance of the topic to public safety. Specifically, our study focuses on workers who are occupationally exposed to toluene, recognising the vital importance of their health and welfare. The aim of our review is to uncover the health effects resulting from different types of toluene exposure, aiming to shed light on this critical issue and contribute to the improvement of policies to ensure the safety and well-being of these workers. Through our findings, we aspire to raise awareness and advocate for changes in current practices, ultimately promoting a safer environment for those exposed to toluene in occupational settings.

Results

Acute exposure effects

According to the Occupational Safety and Health Administration (OSHA), using a toluene reference concentration of 5 mg/m³, acute exposure has an acute minimal risk level of 2 ppm for exposures ranging from 1 to 14 days.¹¹ A spectrum of health implications spanning from cardiac arrhythmias to neurological effects are presented with acute toluene exposure.

Cardiovascular system

Cardiac arrhythmias can be a result of acute toluene exposure, including bradyarrhythmias and tachyarrhythmias, with bradyarrhythmias occurring shortly after toluene exposure, followed by more commonly observed tachyarrhythmias.¹²

Vestibular system

Organic solvent exposure to toluene can result in vertigo, a characteristic of vestibular lesions. However, lacquer factory workers exhibited minimal incidents, possibly due to their exposure duration.¹³

Nervous system

Sparsely documented in the literature are cases of cerebral ischaemic stroke following toluene exposure. However, a case study of a chemical glue factory worker revealed a potential link between high serum toluene levels, occupational exposure and stroke development, a consequence likely to be mediated by sensitisation of vessel receptors leading to vasospasm.¹⁴

Furthermore, neurotoxicity-induced confusion is prompted by acute toluene exposure, and short-term exposure to toluene concentrations of 100pm or higher can lead to neurotoxicity manifesting as confusion, headaches, seizures, visuomotor impairments, vertigo, and visual memory deficits.^{12 15}

In chronic exposure scenarios, symptoms range from headaches, fatigue and irritability to paraesthesia and sleep disturbances; however, in a case study, the same symptoms for a patient were correlated to the characteristics of acute toluene solvent intoxication. The patient had been employed for almost 2 months in a poorly ventilated work environment, and most of her symptoms resolved over the weekend.¹⁶

Chronic exposure effects

Using the same criteria as the OSHA, chronic exposure is defined as reaching a chronic minimal risk level of 1 ppm for periods exceeding 365 days.¹¹ Multiple studies have underlined the impact of chronic toluene exposure on human health.

Nervous and vestibular system

Disturbances in the vestibular system were investigated in workers from various sectors, revealing balance impairments and considerable attributions between exposure duration and vestibular dysfunction, which seemed to increase if the exposure was long-term.¹⁷ A case study regarding prolonged occupational toluene exposure was linked to acute ischaemic stroke. MRI results revealed damaged white matter and neurobehavioural impairments.¹⁴

Batik workers manifested neuropsychological symptoms, including headaches, insomnia and concentration difficulties. Repeated toluene exposure will eventually impact the central nervous system (CNS), and prolonged occupational exposure, even at low levels, can be detrimental and can lead to specific biomarker changes, such as increased metabolite levels of hippuric and methyl hippuric acid, which over time may contribute to serious health outcomes.^{18 19} Further to that is the correlation of toluene exposure to peripheral neuropathy. Moreover, workers in a bone glue factory in Egypt working for 5 years or longer indicated positive urinary hyaluronic acid (HA) and abnormal electromyography results, potentially contributing to paraesthesia.²⁰ Although the presence of increased HA levels is not specific to toluene exposure, but may also be present after exposure to other volatile aromatic hydrocarbons such as benzene, ethylbenzene and xylene, the increased levels may potentially contribute to the onset of the observed neurological symptoms.

Chronic exposure to toluene can also induce optic neurotoxicity, causing visual impairment via impaired optic nerve function. This was shown in an employed painter for 25 years with no previous ocular complaints.²¹ Impairments of sympathetic and peripheral nerves in workers are probable. Deterioration of memory and attention and cerebral atrophy have also resulted from sub-chronic toluene exposure. Therefore, chronic toluene exposure, as stated previously, induces neurological manifestations causing personal discomfort.¹⁵

Defects in colour discrimination and subtle changes in blue-yellow colour vision were found to be the result of permanently exposed workers, previously stated in the ocular symptoms of the nervous system section.²² Sympathetic and parasympathetic activity was also observed to be influenced by long-term toluene exposure, indicating the toluene effect of impairing cardiac autonomic function. As exposure increases, the activities in both systems diminish. Though arrhythmias were not detected, the maximum heart rate was considerably lower in the exposed group compared with the control in one study.²³ In a study by Tunsaringkarn et al, chronic toluene exposure induced fatigue, headache, and cognitive impairments.²⁴ It is also associated with cognitive decline and white matter lesions.²⁵

Respiratory effects

Respiratory symptoms and complaints of cough and colds were observed when investigating footwear craftsman workers.²⁶

Auditory effects

A study by Ahmadi Asour et al showed the synergistic effects of toluene and noise exposure, resulting in ototoxicity. The risk of hearing loss and impairment was more remarkable in simultaneous exposure, and the study ruled that the work site conditions did not protect the workers against hearing loss.²⁷ Similarly, in a study by Zamyslowska-Szmytke et al, hearing impairment was prevalent in 42% of toluene-exposure workers attributed to its combined exposure to noise.¹³

Metabolic effects

Research emphasises the substantial influence of obesity on CYP2E1 activity regulation. Long-term cumulative exposure to toluene results in potential chronic and irreversible effects on CYP2E1. Individuals with a lengthy exposure duration and diminishing enzymatic activity are at a notable disadvantage. Alongside this, the consequences of increased reactive oxygen species (ROS) due to toluene have been linked to subclinical damage and nervous system dysfunction.²⁸

Genotoxicity

As shown in the reviewed studies, DNA damage correlated with age, exposure duration and daily exposure to paints. Higher levels of molecular damage were associated with increased correlations, respectively.²⁹ Elevations in sister chromatid exchanges in lymphocytes of toluene-exposed individuals were observed. CYP genotypes have been linked to findings outlining their influence on genotoxic and lymphocytic chromosomal damage.^{30 31} Numerous studies have suggested a genotoxic effect associated with chronic occupational toluene exposure.³²

Autoimmune effects

Finally, regarding the chronic effects of toluene, a study by Chaigne et al found that high cumulative exposure to toluene among other solvents was associated with significantly increased ORs among all Primary Sjogren’s syndrome (pSS) patients. This observation was consistent across pSS patients with anti-SSA or anti-SSB antibodies and those with extra-glandular symptoms. These findings suggest that long-term or high levels of exposure to these solvents may be particularly detrimental to the development and progression of pSS.³³

Short-term effects

Some effects manifest themselves in the short term following exposure to certain solvents, including exposure to toluene. In a case report assessing a myoclonic seizure that had occurred to a patient before the diagnosis of chronic toxic encephalopathy (CTE), some effects had been revealed, which manifested shortly after toluene exposure. These included symptoms of intense headache, fatigue, asthenia, irritability, the feeling of drunkenness, nausea and paraesthesia in the patient’s feet. Additionally, the patient was found to suffer from sleeping disturbance, either difficulty falling asleep or sleepiness. However, she correlated all these characteristic symptoms of acute solvent intoxication with her employment for almost 2 months in a poorly ventilated work environment, and the majority of her symptoms resolved over the weekend. It is worth noting that short-term effects may refer to effects that occur shortly after toluene exposure and are not necessary on first exposure to toluene, as was the case with the patient investigated in the case report, as she had a history of 20 years of chronic exposure to organic solvents, indicating that repeated exposure may result in inducing some of the short-term effects reported which may resolve soon after.¹⁶

Long-term effects

Long-term effects from toluene exposure have been reported in the literature, including mild symptoms such as headaches and more severe outcomes such as epileptic seizures.^{16 24} Fatigue, headache and throat irritation are prevalent in workers who have undergone chronic toluene exposure, that is, those who have been occupationally exposed to toluene for a minimum of 3 months.²⁴ Headaches and nausea have also been noted as a manifestation of chronic toluene exposure but may improve in the months following toluene-exposure cessation.²⁵

Disturbances of the vestibular system were also reported as a long-term effect due to toluene exposure in a study by Hosni et al¹⁷ using dynamic posturography among workers in the textile manufacturing industry. The sensory organisation test in dynamic posturography used to assess vestibular disturbances revealed lower performance in the toluene-exposed group, indicating vestibular abnormalities. The long-term effects from toluene exposure were substantiated by the negative correlation between the duration of exposure to toluene and dynamic posturography, indicating that prolonged exposure damages the vestibular system and worsens balance assessment findings among workers exposed to toluene in the long term. Furthermore, an increase in the frequency of dizziness and vertigo was also revealed due to long-term toluene exposure.¹⁷

Neurological effects have also been demonstrated as long-term manifestations of exposure to toluene. The primary effect of toluene on the CNS is high cerebral perfusion.¹⁶ Other effects on the neurological system that organic solvents like toluene may evoke include dizziness, which is common in CTE.¹³ Long-term exposure to toluene also induces damage to the myelin sheath in nerves. This can result in neurotoxin risks involving dementia, concentration difficulties, sleep disturbances and agitation.³⁴

Haematologically, low platelet counts have been consistent with long-term low-level toluene exposure in workers. In a study by Shih et al,¹⁵ low platelet counts were deemed to be due to disturbances of platelet synthesis, increased platelet damage or transient hyper-agglutination. With current findings, monitoring platelet count appears to be an efficacious method to monitor continuous toluene exposure at low levels closely.¹⁵ Nevertheless, techniques such as monitoring urine biomarkers, hippuric acid level or measuring CYP2E1 activity, for instance, may detect toluene exposure earlier than symptomatic presentations.^{18 19 28} Finally, with relation to genotoxic effects, occupational exposure to toluene for a minimum of 6 months is associated with a significantly higher frequency of sister chromatid exchanges and lymphocytic chromosomal damage.³¹

Low-dose effects

Low doses of toluene exposure have also been found to induce specific manifestations within workers. Sympathetic and peripheral nerve dysfunction are some of the outcomes of continuous low-level toluene exposure, which could reduce peripheral nerve conduction velocity, affecting cardiac parasympathetic activity.¹⁵ In another study, increased levels of hippuric acid, a biomarker used to monitor exposure to toluene, among other VOCs, resulted in notable changes in gene expressions, indicating that molecular responses can be triggered even with low doses or levels of exposure to VOCs, such as toluene.¹⁹ Furthermore, prolonged low-dose exposure may result in changes in gene expressions that are documented to influence processes like carcinogenesis and the nervous system, involving cognitive function and conditions such as Parkinson’s disease. Such areas are particularly susceptible to prolonged VOC and toluene exposure and may be precipitated even at low doses.¹⁹

High-dose effects

When exposed to high concentrations of toluene in confined spaces, severe consequences can arise, even if the exposure is short-term. Acute muscle injury and renal failure were reported in a study emphasising the importance of improving workplace conditions, using personal protective equipment (PPE), and early medical intervention when intoxications emerge.³⁵

High dosage toluene exposure was found to influence the autonomic nervous system. Compared with the control group, the toluene-exposed group exhibited reduced sympathetic and parasympathetic activity. Increased exposure to toluene led to increased vagal activity markers and a diminishing of both the sympathetic and parasympathetic systems.²³

Next, a case–control study examined the risk of bladder cancer due to occupational exposure in Nordic countries. A link between higher exposure levels to toluene correlated with an increased risk of bladder cancer, while no significant effects were observed at lower exposure levels.³⁶

In a study of furniture workers and toluene exposure, olfactory dysfunction was prevalent, with the Sniffin’ Sticks test revealing impairments in 84.1% of participants. This dysfunction manifested as a 75% impairment in odour threshold, 25.0% in odour discrimination and 63.6% in odour identification. A 12.5-fold greater incidence of olfactory dysfunction was discovered in high-risk groups exposed to toluene.³⁷

Reversible effects versus irreversible effects

As previously stated, chronic toluene exposure often results in headaches and nausea, which has been shown in one case study that these manifestations may gradually subside and improve in the following months on cessation of toluene exposure.²⁵ To possibly prevent rather than reverse the effects of toluene toxicity, a study emphasises the importance of PPE to mitigate risks and prevent adverse health effects.³⁴

Conversely, some effects of toluene exposure are shown to be potentially irreversible due to enzymatic inhibition. Hepatic CYP2E1 enzymes metabolise toluene on absorption. Therefore, its activity is a valuable marker for assessing toluene exposure. Other VOCs such as benzene, acetone and more can result in enzymatic inhibition, which likely decreases liver CYP2E1 activity. The inhibition could be of a competitive or non-competitive nature arising from the presence of multiple substances metabolised by the enzyme due to environmental, occupational or intentional exposures. Therefore, toxicological manifestations will arise due to elevated levels of toluene and other substances due to the inhibition.²⁸

Discussion

In reviewing the literature on the characteristic effects of toluene on workers’ health, we found that toluene exerted short-term and long-term, low-dose and high-dose, reversible and irreversible, and multisystemic effects. However, this is not novel information, with this being corroborated by agencies implicated in occupational health, such as the Centres for Disease Control and Prevention (CDC) and Safe Work Australia, among others.^{6 38 39} What remains unverified is the establishment of specific toluene thresholds corresponding to these diverse attributes of toluene exposure. Due to discrepancies among different sources, varying and inconsistent data regarding exposure limits has been presented.

Our integrative review revealed that the manifestations of toluene exposure within occupational settings are contingent on variables such as exposure duration, dosage and frequency. It was evident, for example, that acute toluene exposure in high doses had severe outcomes resulting in cardiac and neurological abnormalities.¹² Sparsely noted in the literature was the incidence of stroke due to vasospasm following high serum toluene level and occupational toluene exposure.¹⁴ However, this association requires further investigation. In contrast to the severe adverse effects of acute toluene exposure, chronic exposure arguably was met with milder repercussions such as vestibular dysfunction, balance impairments and other cognitive disturbances.¹⁷ Nevertheless, it should be noted that longer durations of chronic exposure will cause increased damage and harm.¹⁷ The consensus of a multitude of sources affirms that the neurotoxicity, genotoxicity and DNA damage associated with chronic occupational toluene exposure exhibits significant and profound effects. DNA damage, for instance, correlated with age, exposure duration and daily exposure to paints. Higher levels of molecular damage were associated with increased correlations, respectively, and inevitably increased risk for cancer and malignancy.²⁹ Nevertheless, the potential carcinogenic implications of chronic toluene exposure are not corroborated by occupational health agencies like the CDC and Safe Work Australia. Toluene is also not classified as a carcinogen by the Globally Harmonized System of Classification and Labelling of Chemicals and is not classifiable by the International Agency for Research on Cancer.^{38 39} This potential linkage between toluene exposure and malignancy remains a subject of inquiry, necessitating further comprehensive investigations.

The underlying mechanisms in the pathogenesis of the multi-varied manifested effects seen on exposure to toluene can be explained using toluene’s toxicological properties and the underlying pathophysiological mechanisms that occur. Toluene’s effects on the nervous system can be explained by toluene’s lipophilic nature, which facilitates its penetration of the blood-brain barrier, consequently disrupting the integrity of neuronal membrane function and neurotransmitter dysregulation, causing effects such as dizziness and cognitive dysfunction seen in acute and chronic occupational exposure.⁴ Additionally, it has been demonstrated that toluene can cause myelotoxic effects and cerebral white matter damage, further explaining the neurotoxic effects.⁴⁰ Although the pathophysiological effects of toluene and other solvents on the vestibular system have not been extensively explored in the literature, previous animal and human studies have shown similar sites of action where toluene appears to act on the cerebellum, causing pathological nystagmus and the possible effects on the vestibule-ocular reflex.⁴¹ Next, cardiovascular effects may be attributed to toluene’s effects, such as vasospasm and oxidative stress-induced endothelial dysfunction in acute high-dose exposures, explaining the development of ischaemic events, which can lead to arrhythmias and strokes.⁴² Oxidative stress caused by toluene has been suggested to be the central mechanism by which it exerts its multisystemic effects. The increased generation of ROS during toluene’s metabolism can cause widespread damage to various cellular components, such as lipids and proteins, causing the observed systemic effects in exposed workers.^{43 44} This exact oxidative stress mechanism also explains the genotoxicity associated with chronic toluene exposure, where ROS can induce damage to cellular DNA, explaining the increased risk of malignancies.⁴⁴ Nevertheless, further mechanistic studies are required to explore the exact molecular pathways in which toluene induces damage to different organ systems to help better understand the manifestations of occupational exposure.

How much toluene one is exposed to can determine the chemical’s effect, highlighting the importance of there being limits on how much toluene workers should be exposed to.⁶ Limits on occupational toluene exposure vary across jurisdictions, and even where they are stipulated in legislation, they are not always enforced. Furthermore, in some of the studies we reviewed, deleterious health effects were demonstrated in workers when exposed to toluene at a level that was permissible according to local law, particularly with exposure occurring over longer durations. Consequently, legislation must consider magnitude and duration when setting limits on occupational toluene exposure. Furthermore, the feasibility of lowering said levels of exposure to toluene stipulated in legislation should be explored, and it should be ensured that workplaces’ capacities are compatible with what the law commands. Based on the review’s results, it is evident that the current threshold toluene exposure limit of 20 ppm suggested by organisations such as the American Conference of Governmental Industrial Hygienists is not sufficient to prevent inducing harm to the workers’ health as portrayed by some of the investigated studies’ results. These include studies conducted by Türkoğlu et al, Ahmadi Asour et al and Jiménez-Garza et al, where the recommended limits had been discussed.^{12 27 28} Other occupational health agencies, like the CDC, quote specific standards and guidelines suggested by the OSHA of the United States Department of Labour on the exposure limit and duration. OSHA suggests a permissible exposure limit of 200 ppm to be averaged over an 8-hour work shift and a short-term exposure limit of 500 ppm with a maximum duration of 10 min. Evidently, a pressing requirement emerges for the revision and standardisation of toluene exposure limits in light of the disparities and inconsistencies present within these figures and datasets. This review advocates that the relevant authorities conduct a thorough reassessment of the toluene exposure limits based on current studies. It is imperative to set an updated and more stringent recommended exposure limit encompassing diverse aspects of toluene exposure and its health effects, including dosage, duration and frequency. These revised limits should be defined to outline specific thresholds associated with different health effects and characteristics of occupational toluene exposure.

The risk posed by occupational exposure to toluene can be circumvented using PPE. One of the studies reviewed indicated occupational toluene exposure damaged DNA and found that said damage was mediated using PPE.²⁹ Another study we reviewed found that PPE helped workers be protected from toluene-induced neurotoxicity.³⁴ However, mandating PPE in the workplace can be challenging, particularly as noncompliance with PPE is commonplace in industrial settings. Policy pertaining to health and safety in the workplace may serve as a target through which said lack of compliance can be addressed, such as by stipulating the ramifications for noncompliance with PPE. Crucially, policy reform should be paired with policy enforcement. In making mandates for PPE attainable for workers, as well as in preserving PPE’s efficacy, education, and training about the use of PPE are critical.⁴⁵

Since maintaining compliance with PPE is difficult, other important measures should be implemented, including proper ventilation, education and enforcing legislation. Those factors would help mitigate exposure more effectively. Poor ventilation in the workplace promotes workers’ vulnerability to toluene, as well as vulnerability to other occupational pollutants. Therefore, ensuring the workplace is ventilated is essential. Said ventilation can be natural, such as through doors and windows, or mechanical, such as through air-supplying machinery. National policy can aid in ensuring workplaces country-wide are well-ventilated.⁴⁶ Moreover, education in the workplace can help ensure that workers are aware of the implications of toluene exposure and how they can protect themselves. Education is effective but also low-cost, making it something that can easily be implemented in the workplace, regardless of these workplaces’ capacities.⁴⁷ Finally, country-wide legislation can help ensure that workplaces are more accountable for the health and safety of their workers. However, there must be agents to bring these laws into action, whether that be occupational health specialists or labour inspections.^{48 49}

Strengths and limitations

This is the first comprehensive review, to the best of our knowledge, to collate and analyse the distinct effects of various types of occupational exposure on workers’ health, offering a thorough comparison in a single paper. Using a modified integrative review framework by Whittemore and Knafl enabled a holistic approach by incorporating diverse study designs; however, several limitations must be acknowledged. First, given the nature of integrative reviews, including both empirical and theoretical data could dilute the validity of claims and increase bias. While our aim was maximum exploration, including a broad range of studies may reduce the overall robustness of this review’s conclusions due to data inconsistencies. Furthermore, excluding individuals under 18 and those over 65 neglects the potential impacts on paediatric and geriatric populations. Immunocompromised individuals, such as pregnant workers or their fetuses, were not explored even though the reproductive and developmental effects of toluene on said populations have been documented in studies of non-occupational exposure, which may serve as a suitable research subject in the occupational setting. toluene’s teratogenicity has also been studied in the non-occupational setting.⁵⁰ Ethical considerations on said topics limit the scope of this review thus, further inquiry into toluene’s effect on worker health in wider populations may be an appropriate subject.⁵¹ Our review limited studies to those published in English between 2010 and 2023, which could result in omitting relevant studies outside of these constraints that may provide valuable insights. The focus on specific biomarkers such as hippuric acid, platelets or CYP2E1 activity also presents challenges, as these can be influenced by a variety of factors unrelated to toluene exposure. We encourage future research to address these gaps by aiming to employ larger, more diverse populations and biomarker assessment. More primary investigations of toluene’s effect on carcinogenesis, cancer, nephrotoxicity and pSS are motivated to strengthen said links as in said papers due to particular sparsity.

Conclusion

This integrative review highlights the acute, chronic, short-term, long-term, low-dose, high-dose, reversible and irreversible effects of toluene exposure on workers’ health, ranging from common symptoms like headache, fatigue and nausea to more adverse system-oriented effects from cardiovascular to neurological deficits. The results also demonstrate the different manifestations of toluene toxicity associated with the duration, dose and frequency of occupational exposure. High-dose exposure will influence different types of effects than those of lose-dose exposure. These findings can be used to update workplace guidelines and protect workers by implementing strategies like mandatory use of PPE, better ventilation and education of workers to mitigate the risks of toluene exposure. Further research is required to establish a revised novel recommended exposure limit to account for the findings found in this integrative review. We also encourage the exploration of gaps present in current literature regarding toluene’s effect on vulnerable groups such as children and pregnant women, as well as reproductive, teratogenic and developmental effects.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.