Clinical Symptoms, Neurological Signs, and Electrophysiological Findings in Surviving Residents with Probable Arsenic Exposure in Toroku, Japan

Questionnaire

From 1974 to 2005, all participants were administered a self-reported questionnaire asking whether they had experienced certain subjective symptoms or comorbidities that lasted for more than 1 year. The subjective symptoms comprised sensory disturbance, skin disturbance, upper and lower respiratory symptoms, hearing symptoms, visual symptoms, headache, dizziness, gastrointestinal symptoms, vascular disturbance, teeth problems, olfactory dysfunction, tremor, anemia, liver/gallbladder symptoms, wasting, and taste disturbance. The comorbidities comprised neuropathy/radiculopathy, hypertension, respiratory disorders, gastrointestinal disorders, cardiac disease, cataracts, skin disease, liver disease, and diabetes mellitus. We analyzed the relationship between these parameters, sex, and arsenic exposure during infancy and early childhood. We defined “infancy and early childhood” as the period from age 0 to 9 years and evaluated the long-term effect of arsenic exposure in participants who spent at least 1 year of their infancy and/or early childhood in Toroku.

Evaluation of Sensory Dysfunction

We evaluated sensory impairment with a sharp toothpick for pain, test tubes containing water at 0 or 50 °C for temperature, soft tissue paper for touch, and a 128 Hz tuning fork for vibration. The severity of sensory disturbances was graded as follows: “0,” almost normal sensation; “1,” sensation decreased by less than half; and “2,” sensation decreased by more than half.

Longitudinal Study of Sensory Dysfunction

To evaluate long-term sensory dysfunction by neurological examination, we selected participants who had undergone the Toroku Medical Examination more than ten times for more than 10 years. For nerve conduction studies (NCS), which were first conducted in 2003, we enrolled participants if they had undergone NCS more than three times. For both types of analyses, participants were excluded if they had diabetes mellitus, alcoholism, or a past history of gastric resection.

NCS Protocol

NCS were conducted using a Neuropack MEB2200 electromyogram apparatus (Nihon Kohden, Tokyo, Japan). Motor NCS were performed on the median and tibial nerves. The stimulus site was 3 cm proximal to the wrist crease and elbow in median nerve studies and just lateral to the medial malleolus and popliteal fossa in tibial nerve studies. Antidromic sensory NCS were conducted on the median and sural nerves. In the median nerve study, the recording site was the index finger with the stimulation at the wrist, and in the sural nerve study, the recording site was the lateral malleolus with stimulation 14 cm proximal to the mid-calf.

This study protocol was approved by the Ethics Committee of the University of Miyazaki, with a waiver of written, informed consent obtained from participants with chronic arsenic exposure, and was performed in accordance with the Declaration of Helsinki.

Questionnaire Results: Subjective Symptoms and Comorbidities

Table 2 summarizes the cumulative questionnaire data regarding subjective symptoms and comorbidities. Sensory disturbance was the most common symptom (97.8%), followed by skin disturbance (95.6%), upper respiratory symptoms (90.5%), hearing (89.1%), and visual symptoms (89.1%). Frequent comorbidities included neuropathy/radiculopathy (43.1%), hypertension (33.6), respiratory disease (32.1%), and gastrointestinal disorders (29.2%). Twenty participants (14.6%) had no comorbidities. In an analysis of the questionnaire data by sex, the only significant finding was that cataracts were significantly more prevalent in females (P = 0.04).

Objective Neurological Findings

Cumulative data of objective neurological findings are summarized in Table 3. Abnormalities in cranial nerves I (olfactory nerve, 27.7%) and VIII (vestibulocochlear nerve, 50.4%), and sensory dysfunction in the bilateral lower distal limbs (28.5%), were common neurological findings in participants with arsenic intoxication, while 37 participants (27.0%) had no neurological abnormalities. Female participants had a higher prevalence of gait disturbance due to joint problems than male participants (P = 0.01).

Clinical Symptoms and Neurological Signs in Participants with Probable Arsenic Exposure During Infancy and Early Childhood

Eighty-nine participants, including 51 males (57.3%) and 38 females (42.7%), were exposed to arsenic during infancy and early childhood, as defined in the Methods. Basic characteristics, such as occupational history, age, and the number of survivors in 2014, were not significantly different between male and female participants (data not shown). In the questionnaire (Table 4), female participants had a higher prevalence of olfactory dysfunction than male participants (P = 0.04). There were no significant differences in other subjective symptoms (Table 4), comorbidities, or neurological findings (P > 0.05; data not shown).

Subjective Symptoms, Comorbidities, and Neurological Findings

Participants with probable arsenic exposure demonstrated various symptoms of intoxication even more than 10 years after exposure cessation. Typical symptoms of chronic arsenic intoxication include neurological and dermatological abnormalities; in contrast to acute poisoning, gastrointestinal symptoms were found to be uncommon in a recent review (Naujokas et al. 2013). In our study, almost all participants developed neurological and dermatological symptoms, and 80% had gastrointestinal symptoms. Moreover, about half of all participants had the following uncommon subjective symptoms and neurological abnormalities: dysfunction of the ears, eyes, or mouth; olfactory disturbance; or memory impairment. Differences in exposure routes may impact which symptoms develop. In our participants, contaminated drinking water was less of a problem than direct exposure of the ears, eyes, mouth, or nose to air containing high concentrations of arsenic. Furthermore, previous studies revealed that chronic arsenic exposure caused eye diseases (See et al. 2007; Sinczuk-Walczak et al. 2010; Chen 2014), hearing impairment (Kesici et al. 2016; Li et al. 2017), oral cavity lesions (Sarwar et al. 2010; Syed et al. 2013), olfactory dysfunction (Ishinishi et al. 1977; Mukherjee et al. 2014), and memory impairment (Tyler and Allan 2014). Arsenic levels in some of our participants’ hair were found to be high when the Toroku Medical Examination was first administered (10 years after exposure ended). It is of interest that participants with probable exposure had high rates of various intoxication symptoms even more than 10 years after exposure cessation.

Workers at the arsenic mine were significantly more likely to be male than female. However, there were no differences in symptoms and neurological findings in males and females except for a higher prevalence of both cataracts and gait disturbance due to orthopedic problems in females. This may be because arsenic pollution existed not only in the mines but also throughout the Toroku valley, in both the air and drinking water. It is unknown why female participants in this study were more likely to develop cataracts, because the prevalence of this condition is generally the same for both sexes (Hirvela et al. 1995). Female participants also tended to have orthopedic problems that led to difficulty walking. This may not be related to arsenic intoxication, because women generally have a higher prevalence of osteoarthritis of the knee and hip (O’Connor 2007). In addition, female participants who experienced probable arsenic exposure during infancy and early childhood were more likely to develop olfactory dysfunction. Previous studies of olfactory problems (Ishinishi et al. 1977; Mukherjee et al. 2014) did not compare males and females, and the reason for the sex difference in this study was unclear.

Longitudinal Follow-Up of Sensory Function

Neurological examination and NCS showed that sensory dysfunction in participants with probable arsenic intoxication worsened over the 40-year follow-up, a period that ended long after the last exposure, although the nerve conduction velocity of the sural nerve gradually improved. With increased age, even people with no comorbidities demonstrate decreased vibration sense in the toes and ankle joints after age 70 (Potvin et al. 1980), as well as reduced superficial sensation (Guergova and Dufour 2011) and impaired NCS (Rivner et al. 2001). In the NCS of participants with chronic arsenic intoxication, Supapong et al. (2004) found no significant difference compared with healthy controls, while other studies demonstrated significantly worse peripheral neuropathy in those exposed to arsenic (Feldman et al. 1979; Lagerkvist and Zetterlund 1994; Mukherjee et al. 2003). Therefore, the impaired sensory function observed in our study may have been age-related rather than due to arsenic intoxication, because the participants were not compared with age-matched controls.

Two different methodologies revealed different results regarding lower limb sensation: NCS of the sural nerve improved, but sensory function evaluated by neurological examination worsened. This discrepancy could not be explained solely by the age-related impairment of large peripheral nerves. Indeed, two studies that evaluated sensory disturbance in residents of Toroku demonstrated central nervous system dysfunction (Mochizuki et al. 2016) and small fiber neuropathy (Kawasaki et al. 2002). Although the detailed mechanisms are unclear, these conditions may have contributed to the gradual sensory impairment.

The authors thank all participants, physicians, laboratory technicians, and officials of Miyazaki prefecture who cooperated with the Toroku Medical Examinations. This study was partly supported by JSPS KAKENHI Grant Numbers 15K08780 and 18K10052 (HM).