YUSHO and YU - CHENG

HISTORY

The fi rst known case of yusho (rice oil disease) involved

a 3 - year - old girl in northern Kyushu, Japan, who had an

acute onset of an acneiform rash (chloracne) in June,

1968. Her family members, followed by other familial

clusters, presented to a single clinic with complaints of

acneiform rash, hyperpigmentation, and eye discharge

over the next 2 months. By January 1969, 325 cases were

reported. After a small minority of patients initially

identifi ed rice oil as the causative agent of yusho, Kyushu

University convened the Study Group for Yusho to

investigate yusho; about 2,000 affl icted patients were

subsequently identifi ed. The clinical features of yusho

included fatigue, headache, cough, abdominal pain,

peripheral numbness, hepatomegaly, irregular menstrual

cycles, nail deformities, and hypersecretion of sebaceous

glands. A fi eld survey of canned rice oil associated the

disease with the use of “ K Rice Oil ” produced or shipped

by the K Company on February 5 – 6, 1968. The

yu - cheng epidemic involved over 2,000 individuals in

Taiwan in 1979, when an accidental leakage of thermal

exchange fl uid resulted in the contamination of rice -

bran oil with polychlorinated biphenyls (PCBs), dibenzofurans

(PCDFs), and quaterphenyls (PCQs). 8 The

clinical features of yu - cheng and yusho were similar.

EXPOSURE

Source

Polychlorinated biphenyls (PCBs) and polychlorinated

dibenzofurans (PCDFs) are thermal heat exchanger

compounds used in food processing machinery. Leakage

of these compounds into rice oils during manufacturing

led to the yusho and yu - cheng outbreaks.

Yusho

Epidemiological studies revealed that 95.7% ( p < 0.01)

of surveyed patients recalled consumption of rice oil

from K Company in Western Japan. A case - control

study revealed rice oil as the only associated etiologic

factor, and a cohort study demonstrated a 64% risk of

yusho in K rice oil consumers compared with no risk for

nonexposed individuals. Food engineers confi rmed the

leakage of dielectric thermal exchange fl uid (Kanechlor

400) containing PCBs into the rice oil. This contaminant

contained PCB compounds, primarily tetra - chlorinated

biphenyls. In 1969, the Study Group initially concluded

that PCBs caused yusho. However, a lack of similar

symptoms (besides chloracne) in PCB workers who had

signifi cantly higher tissue burdens (mean blood PCB

level: 45 ppb) contradicted this conclusion. Furthermore,

the dermatological lesions could not be reproduced in

animals following the oral administration of PCB compounds

or by Kanechlor 400, and the severity of the

clinical features of yusho did not correlate to serum

concentrations of PCB compounds. Therefore, other

compounds (e.g., polychlorinated dibenzofurans) in the

adulterated rice oil probably contributed to the development

of yusho.

Yu - cheng

As with the yusho incident, the suspected causative

agents of yu - cheng were PCDFs rather than PCBs.

Contamination of the cooking oil occurred when PCBs

used for the indirect heating of rice - bran oil leaked

into the cooking oil. Repeated heating of the partially

degraded PCBs produced PCDFs, as well as polychlorinated

terphenyl and polychlorinated quaterphenyl

compounds.

Food Processing

High temperatures ( > 200 ° C) in dielectric thermal

exchange fl uid during the deodorization step of oil refi ning

contributed to the development of yusho and yu -

cheng by degrading PCBs in the contaminated rice

oil to PCDFs, PCDDs (polychlorinated dibenzo dioxins),

and PCQs (polychlorinated quaterphenyls). 14

DOSE RESPONSE

Exposure to toxic contaminants in the rice oil from the

yusho and yu - cheng epidemics was assessed by recording

the lot numbers of purchased oil containers and

comparison of the volume of oil purchased to the volume

of oil remaining in the containers retrieved from affected

households. Consumption of the contaminated rice oil

by household members was estimated by proportional

distribution to each family member. Positive relationships

were observed between estimated individual oil

consumption and incidences of yusho and yu - cheng.

The mean concentrations of PCBs, polychlorinated quaterphenyls

(PCQs), and PCDFs in fi ve samples of contaminated

cooking oil from the yu - cheng outbreak were

62 ppm, 20 ppm, and 0.14 ppm, respectively. The congeners

of these compounds were similar in the cookingoils

from these two outbreaks, but ye - cheng cooking oil

samples contained about 10% of the concentrations of

these compounds found in cooking oil from the yusho

incident along with three to four times lower PCQs/

PCBs and PCDFs/PCBs ratios.

A cross - sectional study of 79 patients with documented

yusho demonstrated a dose - response relationship

between estimated consumption of contaminated

rice oil and the symptoms of extremity numbness, coughing,

expectoration, and the sensation of “ elevated

teeth. ” These symptoms were evaluated by self - administered

questionnaires. Symptoms failing to demonstrate

a dose - response relationship to the estimated ingestion

of contaminated rice oil included fatigue, eye discharge,

fever, headache, dizziness, abdominal pain, swollen

joints, menstrual irregularities, and alopecia. The estimated

mean total intake of PCBs and PCDFs by yusho

patients was about 633 mg and 3.4 mg, respectively,

compared with 973 mg and 3.84 mg, respectively, for yu -

cheng patients.

CLINICAL RESPONSE

Animal studies confi rm a strong association between

high concentrations of PCBs (i.e., at least 60% chlorination)

in diets and the incidence of hepatic carcinomas.

However, no human studies have confi rmed an association

between PCB exposure and cancer. Therefore,

PCBs are listed as probable human carcinogens by the

International Agency for Research on Cancer (IARC)

and the US Environmental Protection Agency

(EPA).

Yusho

Clinical features of this illness included fatigue, headache,

cough, abdominal pain, peripheral numbness, hepatomegaly,

irregular menstrual cycles, nail deformities,

and sebaceous gland hypersecretion. The most common

symptoms were eye discharge, hyperpigmentation (skin,

mucous membranes, nails), acneform lesions, and weakness.

Although the severity of these symptoms has

decreased since the epidemic, follow - up studies of yusho

survivors indicated that these symptoms persisted at

least through 1993. The chloracne resolved relatively

rapidly in children, but hyperpigmentation and hypertrichosis

remained in some patients. Thirteen children

born to yusho - affected mothers exhibited gray - brown

skin discoloration at birth ( “ black babies, ” “ cola - colored

babies ” ), but the discoloration spontaneously disappeared

after several weeks. These babies exhibited no

other symptoms consistent with yusho.

Yu - cheng

The clinical features of yu - cheng and yusho are similar.

Clinical fi ndings include chloracne, hyperpigmentation,

edema, weakness, vomiting, diarrhea, and hepatomegaly.

The acneform eruptions were open comedones, papules,

and pustules with dark heads distributed on the axilla,

extremities, and external genitalia.  Abnormalities

in children of yu - cheng patients included low birth

weights,  prematurity, neurobehavioral changes such as

delayed autonomic maturity, normal menarche with

shortened menstrual cycles, abnormal refl exes, dysfunctions

in visual recognition memory,and decreased

intelligence scores. A 24 - year follow - up study of yu -

cheng victims demonstrated increased mortality from

chronic liver disease and cirrhosis in men, but not in

women. There was an increased incidence of systemic

lupus erythematosus in exposed women in the later

years. The mortality rates for cancers were similar

between the exposed group and the background

population.

DIAGNOSTIC TESTING

Analytical Methods

Gel permeation chromatography and high resolution

gas chromatography/high resolution mass spectrometry

detect and differentiate PCBs and PCDFs in oil samples

and in human samples. Methods that utilize high

performance liquid chromatography/mass spectroscopy

(HPLC/MS) or high performance liquid chromatography/

tandem mass spectrometry (HPLC/MS/MS) reliably

detect the di - oleyl - phenyl amino propanediol ester

(OOPAP) and other acylated phenyl amino propanediol

derivatives (PAPs) in cooking oils. 31 Methods to

detect OOPAP in humans are not available.

Biomarkers

Rice oil from the yu - cheng epidemic contained approximately

3,000 ppm total PCBs. The mean blood concentration

of PCBs in patients with chloracne and

hyperpigmentation was in the range of approximately

5 ppb. There was a linear correlation between the severity

of skin lesions and the total PCB concentrations in

blood samples. Studies of human and animal subjects

indicate that PCB concentrations in the range of 10 –

25 ppm cause similar skin abnormalities. Analysis of

PCBs, PCDFs, and PCQs in contaminated rice - oil

samples collected from factory cafeterias, school cafeterias,

and the families of patients with yu - cheng ranged

from 53 – 99 ppm, 0.18 – 0.40 ppm, and 25 – 53 ppm,

respectively.

Although the specifi c compound associated with

yusho or yu - cheng remains unknown, PCDDs are more

appropriate biological biomarkers for the severity of

yusho and yu - cheng than other polychlorinated hydrocarbons

because the presence of PCDDs in blood

samples indicates exposure to these compounds or

parent compounds as PCDDs do not occur in nature.

These compounds persist in the blood for years.  Clearance

of PCDFs and PCBs in humans is nonlinear with

faster elimination rates at higher concentrations. In

blood samples from 3 yu - cheng patients, the whole

blood elimination half - life of two persistent toxic

congeners, 2,3,4,7,8 - pentachlorodibenzofuran (PnCDF)

and 1,2,3,4,7,8 - hexachlorodibenzofuran (HxCDF) was

approximately 2 1

2 years.  The calculated blood elimination

half - lives of the same PCDF congeners in yusho

patients were more variable with median values near 10

years. In a follow - up study of 359 patients with yusho,

the serum concentrations of PnCDF and PCBs remained

signifi cantly elevated over 35 years after the incident.

The mean blood concentration of PnCDF in exposed

patients was 177.50 pg/g lipids compared with 15.2 ±

8.9 pg/g lipids in the blood of healthy controls. The blood

PnCDF concentration in these patients correlated to

some clinical symptoms of yusho including acneform

eruption, comedones, oral pigmentation, constipation,

numbness in the extremities, and body weight loss.

Follow - up studies indicate that the blood elimination

half - lives are shorter (i.e., about 1 – 5 years) for PCB

congeners than PCDF congeners. Follow - up studies of

blood samples from yusho patients 34 years after the

incident indicate that PCDFs contribute about 65% of

the remaining total toxic equivalents of dioxins (non -

ortho PCBs, mono - ortho - PCBs, PCDDs, PCDFs). 37 In

particular, the mean concentration of some PCDF congeners

were substantially higher than controls including

1,2,3,6,7,8 - HxCDF (3.9 times), 1,2,3,4,7,8 - HxCDF (12

times), and PnCDF (11.3 times). The blood samples

from 165 yu - cheng patients collected 9 – 18 months after

the onset of poisoning contained 10 – 720 ppb PCBs with

a mean value of 38 ppb.

Abnormalities

Yusho and yu - cheng patients occasionally had mild

elevation of serum hepatic aminotransferase concentrations,

but results of most laboratory studies were within

normal ranges. 38 Hepatorenal function is usually

normal.

TREATMENT

The treatment for yusho and yu - cheng is supportive.

Dermatologic changes may persist for several months,

and topical or systemic medications typically do not

alter the time - course of these lesions. Yusho and yu -

cheng patients require long - term follow - up for the

development of liver dysfunction and malignancy.