Mandating manganese biomonitoring: a timely re-evaluation of policies?

INTRODUCTION Manganese (Mn) is a naturally occurring element found in soil, food, water and all living organisms. It is essential to human health for normal development and maintenance of immune and nerve cell functions; it also acts as a cofactor for various enzymes. However, an overexposure to Mn is known to cause dose-dependent progressive and irreversible Parkinsonism-like motor syndrome and manic depressive psychosis, even after its removal from the exposure scene.[1,2] Younger individuals, females and Asians were found to be more susceptible to Mn poisoning,[3] necessitating greater emphasis on protecting these vulnerable populations. OVEREXPOSURE TO MANGANESE In the occupational setting, risk of overexposure to Mn via inhalation of Mn dust is amplified in various industries, including milling of Mn ore, welding, manufacturing of steel alloys, dry cell batteries, paints, fertilisers and water treatment.[2,4] Such industrial overexposure and its consequences remain commonplace globally, such as in Beijing with welders being exposed to Mn levels of up to 128-fold above the limit,[1] Korea where 67.4% of ambient air samples collected at shipyards exceeded the threshold limit value,[5] and the USA where the prevalence of Parkinsonism was found to be 15.6% among welders when compared to 0% among reference workers.[6] In Singapore, although chemical poisoning cases (not differentiated into specific chemicals) are uncommon (three cases reported in 2020,[7] a drop from 11 cases in 2002[8]), there was an increase in chemical exposure above the permissible exposure level (PEL) and consequent rise in the proportion of exposed workers with biological levels exceeding 80% of the recommended biological threshold limit value (BTLV) from 2004 to 2007,[8] which is a cause for concern. In 2016, Ho et al.[4] published a case report of an individual presenting with Mn who had significant occupational exposure to shipyard work and plastic manufacturing, suggesting that overexposure to Mn remains a present threat, especially to individuals working in high-risk industries. Biomarkers, which are integral to the exposure–dose–biological effects continuum, are becoming increasingly important in modern risk assessment frameworks. An ideal biomarker aims to achieve the goals of distinguishing between exposed and non-exposed workers, as well as demonstrating a dose-dependent association with external exposure events and the consequent adverse effects on the target organ.[9] However, till date, multiple studies on blood and urine Mn levels, the two most commonly used biological matrices, have failed to achieve the aforementioned goals.[1,9,10] Poor correlation between these two biomarkers and the Mn exposure levels, as well as significant inter- and intraindividual variability impair the reliability and usability of these biomarkers. One explanation for the poor correlation between blood Mn levels and exposure is its short half-life (<2 h) in blood in contrast to other tissues where Mn accumulates (e.g. half-life >50 days in the brain). This renders blood Mn more effective as an indicator of recent and active, rather than chronic, exposure, and consequent organ-specific toxicity. Furthermore, minimal Mn is excreted through urine (<2%), resulting in little to no significant changes observed in urinary Mn even in individuals with excessive Mn exposure.[10] The significant interindividual and temporal intraindividual variability of the blood and urine biomarkers has been postulated to be secondary to multiple factors, such as variance in interindividual homeostatic controls; circadian and seasonal rhythms of Mn transport protein levels, which in turn are also influenced by the levels of other metals such as iron, copper or zinc; and analytical variability.[11] The lack of reliable biomarkers presently is reflected by the absence of statutory regulations on using Mn biomarkers in the guidelines of most international organisations like the World Health Organization and in countries such as Australia,[12] Korea,[5] Japan,[13] the UK[14] and the USA.[15] Most prominently, the Scientific Committee on Occupational Exposure Limits of the European Commission has concluded that,[16] “Owing to poor correlations with airborne levels and the high individual variability of blood and urine levels… it is not possible to confidently set health-based biological standards for manganese in blood and urine”, which highlights the inadequacies of current biomarkers to support Mn biosurveillance. As such, most countries’ regulatory bodies opted for environmental sampling to ascribe context-specific Mn PEL levels for the protection of vulnerable populations [Table 1].Table 1: Country-specific occupational exposure limits for manganese and its compounds.Interestingly, Singapore continues to mandate Mn biomonitoring as part of its statutory medical screening for exposed workers, citing a urine BTLV of 50 mcg/L.[17] This limit appears to have been used at least as far back as 1988, in reference to the limits set by the UK Employment Medical Advisory Service 1974.[18] The UK advisory service has since been revised to exclude the recommendation of Mn biomarkers on grounds of high variability and poor correlation with airborne Mn levels.[15] Given the advances in Mn research since 1988 — urine Mn has been shown to poorly correlate with environmental Mn exposure, alongside its variable inter- and intraindividual differences — it is timely to review this requirement. The lack of a reliable and validated Mn biomarker alternative may have accounted for Singapore’s inertia to change current guidelines. Though Malaysia has also assigned a urine BTLV of 19 ng/L and blood BTLV of 7.1–10.4 mg/L at present,[19] whether a medical surveillance is required is based on a chemical health risk assessment, and hence, not mandated as routine screen. Separately, Germany also includes a blood BTLV of 15 mcg/L, though it is used for the general populace and not occupationally exposed individuals.[16] Given the severe clinical consequences of Mn poisoning, many studies have been conducted to look for alternative reliable biomarkers, including saliva, blood-specific components, hair, nail, teeth, bone and cerebrospinal fluid (CSF). Aside from high individual variability issues, external contamination of samples (e.g. hair and nail) and technical challenges in the sampling of certain biological specimens (e.g. teeth and CSF) have impeded the search for a reliable and easily accessible biomarker.[10] However, among them, erythrocyte Mn/iron ratio, brain magnetic resonance imaging and bone sampling have shown promising results in correlation with airborne Mn concentration and biological effects, though more studies are required for validation of these modes of detection for broader use.[1,10] To the best of our knowledge, till date, no studies have examined the national Mn screening guidelines of various countries in light of advances in Mn biomonitoring research. Given the poor correlation between Mn exposure and the levels of Mn in blood and urine, a policy review should be considered by countries that continue to rely on these biomarkers for occupational biosurveillance. This is especially so since such a requirement necessitates additional cost and manpower and may give a false sense of security to high-risk groups, which may, in fact, exacerbate persistent chronic exposure and render a higher occupational exposure risk to the worker. Environmental surveillance for Mn has been accepted as the first-line screening modality of exposed workers in many countries. Subsequent assessment of individuals with high Mn exposure exceeding guidelines for recommended environmental levels, for example, 8-h time-weighted average threshold limit value of 1 mg/m3, may then include a clinical evaluation of signs and symptoms of Mn toxicity and appropriate management as needed. CONCLUSION The poor correlation of blood and urine Mn levels with environmental Mn exposure and their wide inter- and intraindividual variability render them unreliable as biomarkers. This is reflected in present international consensus to move away from Mn biomonitoring in occupationally exposed workers, suggesting that it may be timely for countries with statutory Mn biomonitoring to review these requirements. Although Mn biomonitoring remains low in the hierarchy of controls in reference to elimination and substitution, it is still crucial to address it, as biomonitoring complements and augments substitution in the promotion of more robust work safety measures. With the recent advances in Mn research and potential promising Mn biomarkers with better correlation to exposure levels, biomonitoring may eventually be internationally adopted. However, further research and validation still need to be done for these novel biomarkers before any could be adopted for incorporation in national and international standards. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.