Background
n-Hexane, with a molecular formula of C
6H
14, is a colorless liquid with a disagreeable odor. It is miscible with lipophilic organic solvents and is extremely volatile; therefore,
n-hexane is widely applied in the production of adhesives, inks, and lacquers, and coating and cleaning agents. It is also used to extract vegetable oils for human consumption and as a substitute for benzene in solvent applications [
1]. In addition to concerns regarding its inflammable and explosive nature,
n-hexane is notorious for its neurotoxicity.
In the 1960s, several cases of
n-hexane-induced polyneuropathy were reported in poorly ventilated polyethylene laminating plants and a pharmaceutical plant in Japan [
2]. Subsequently, this neurotoxic disease was found to be associated worldwide with occupations such as furniture making [
3], printing [
4], shoe or bag manufacturing [
5‐
7], electronic device manufacturing [
8], or other types of work where
n-hexane-containing adhesive agents were applied [
9‐
12]. Outbreaks were also reported in Taiwan in workers engaged in press proofing [
13], ball manufacturing [
14], and printing [
15].
Due to its known neurotoxicity, preventive measures have been implemented in most industrialized countries. The use of
n-hexane is declining, and it is largely being replaced with other less toxic solvents [
16]. However, occupational
n-hexane intoxication continues to occur in Taiwan occasionally. The presented case is the first case in the Chinese herb industry in Taiwan. Chemical exposure in Chinese medicine pharmaceutical plants could be an emerging issue that may endanger the health of workers.
Discussion
Considering the clinical manifestations, high levels of n-hexane in the workplace, appropriate temporality of the relationship between exposure and disease, and exclusion of other causes, our patient’s polyneuropathy was closely associated with occupational exposure to n-hexane.
Although polyneuropathy due to occupational n-hexane exposure has been reported worldwide, this is the first report in the Chinese herb industry in Taiwan. Herbal medicines have been commonly used for health promotion and the treatment of diseases in Asia and Africa for centuries. Preparation of herbal formulations has become a special industry in modern times with the advent of scientific and industrialized manufacturing processes. Many studies are available on the safety of herbal medicines for consumers; however, occupational chemical exposure during preparation also presents a crucial topic for investigation.
The neurotoxicity of
n-hexane may occur in both the peripheral nervous system and central nervous system (CNS). Peripheral neuropathy is characterized by symmetrical progressive distal sensory and motor impairment. Mostly, the initial symptoms are numbness and a burning sensation in the toes and fingers, followed by distal limb muscle weakness [
1]. Axonal degeneration and focal demyelination can be detected using electrophysiological studies with findings such as reduction of nerve conduction velocity, focal conduction block, prolongation of distal latencies, and amplitude reduction of compound muscle action potentials, particularly in the lower extremities [
7,
8,
20,
21]. Spontaneous activities, such as fast firing and high-amplitude polyphasic motor unit potentials, are common [
1]. CNS conduction abnormalities can be detected in evoked potential studies, or assessed by calculating transcranial magnetic stimulation and spinal nerve root stimulation [
21,
22]. Some patients revealed signs of CNS dysfunction such as spasticity of the lower limbs and increasing deep tendon reflexes [
23]. Our patient had typical clinical presentations and electrophysiological abnormalities, but without evidence of CNS involvement.
A potential neurotoxic metabolite of
n-hexane is 2,5-hexanedione (2,5-HD), which acts as a biomarker associated with
n-hexane exposure [
24]. Good correlation was found between the TWA
n-hexane air concentration and end-of-shift 2,5-HD level in the urine of the patient [
25]. The recommended biological exposure index (BEI) value of the ACGIH for the free form of 2,5-HD in urine is 0.4 mg/L, corresponding to a
n-hexane exposure less than TWA 50 ppm [
18]. The 2,5-HD was not a convenient biomarker because the pretreatment of the urine sample is quite complex, and the measurement of 2,5-HD requires advanced instruments, such as GC-MS and adept laboratory workers [
25]. The aminoderived pyrroles and thiol-pyrrole conjugates in urine are potential alternative biomarkers of
n-hexane exposure in the current study [
26,
27].
The prognosis of
n-hexane-induced neuropathy is believed to be good and tends to be biphasic with “coasting” of 2 to 3 months, followed by a slow recovery for approximately 1 to 2 years after the cessation of exposure to
n-hexane [
1]. In the electrophysiological follow-up of 25 patients with chronic peripheral neuropathy induced by occupational
n-hexane exposure, the recovery of motor nerves was superior to that of the sensory nerves, and upper limbs recovered faster than the lower limbs [
8]. Cessation of exposure is the only way to treat
n-hexane-induced polyneuropathy. Although we had no further electrophysiological follow-up of our case, his symptoms had recovered gradually after cessation of exposure. Detailed history taking is essential not only for early recognition of occupational intoxication, but also to prevent workers from developing further adverse effects.
The lack of a lumbar puncture survey and biomarker data are limitations of this case; however, the diagnosis of n-hexane-induced peripheral polyneuropathy is not controversial. We have strong evidence of occupational exposure and our patient’s recovery after removal of exposure.
To prevent similar occurrences, the use of toxic chemicals or substances should be well managed. We must consider that no chemical is safe. Risk assessment, risk ranking management procedures, workplace monitoring, chemical handling training, and health education should be included in the management of chemicals or toxic substances. Employers, chemical importers, or suppliers cannot provide any excuse for a lack of knowledge regarding the chemicals used on-site, including their properties and hazards. They should take complete responsibility for following the instruction for hazard control and should protect the health of workers.
Poor ventilation in the workplace has been one of the major factors in almost all cases reported worldwide [
25], and a similar situation was also found in our case. Although the room had been reconstructed with a ventilation system, the workplace
n-hexane levels considerably exceeded the PEL. Industrial control of exposure includes not only the installing of ventilation equipment but also making it work effectively. There are two control alternatives in the case, namely enclosing the mixing tank and venting out hexane vapors and installing a proper hood at the end of the exhaust pipe.
Personal protective equipment is the least line of protection for workers’ health from exposure to various hazards. n-Hexane is present as liquid or vapor under normal temperature and pressure; thus, workers were exposed to n-hexane in the workplace through inhalation and dermal contact. In our case, workers were provided with a mask and gloves for protection from organic compounds; however, our patient avoided using them. The employer or the supervisor should undertake the responsibility of supervising and educating workers. Workers should be instructed not only to wear tight-fitting masks in the mixing room, but also to replace or repair the respirator if vapor or gas leaks are detected.
Acknowledgements
We thank Ming-Chang Tseng and Kuo-Jung Ho for case information collection. This manuscript was edited by Wallace Academic Editing.