World Health Organization estimates of the global and regional disease burden of four foodborne chemical toxins, 2010: a data synthesis

Cyanide in cassava

Cassava is an important staple for over 800 million people in approximately 80 countries, mostly in sub-Saharan Africa but also in Asia, the Pacific, and South America²⁰. Cassava tubers contain a varying quantity of cyanogenic glucosides which protect the root against attack by animals and insects. Appropriate processing before consumption can reduce cyanogenic glucoside content of cassava. When high cyanogenic cassava is not processed correctly, high dietary cyanide exposure occurs. This often happens during times of famine and war. Cyanide in cassava is associated with acute cyanide poisoning and several diseases including konzo²¹. Worldwide reports exist of acute poisoning from cyanide in cassava²¹ exist, but the data are inadequate to make burden estimates. The data are sufficient, however, to make burden estimates of konzo. Konzo is an irreversible spastic paraparesis of sudden onset, associated with the consumption of bitter cassava^22,23 and a low protein intake²⁴. It is a disease of extreme poverty. Konzo mostly occurs in epidemics, but sporadic cases are also reported. The case definition includes the following criteria: (1) a visible symmetrically spastic abnormality of gait while walking and/or running; (2) a history of abrupt onset (less than one week), followed by a non-progressive course in a formerly healthy person; (3) bilaterally exaggerated knee and/or ankle jerks without signs of disease in the spine^24,25.

Because konzo mostly affects remote rural areas where health infrastructure is poor or non-existent, many cases remain undiagnosed or unreported, so the true burden of disease remains unknown. No cases have been reported from urban areas. A total of 2376 konzo cases have been reported in 5 countries in Africa (Cameroon, Central African Republic, Democratic Republic of Congo [DRC], Mozambique, and United Republic of Tanzania)²¹, corresponding to 149 cases per year for 122 million people. Dividing the average annual number of cases for each country by the corresponding country population produces an observed incidence ranging from 0.043 to 0.179 per 100,000. The degree of underestimation is difficult to determine as konzo occurs in rural areas, often under conditions of war, and the disease is not notifiable. The only reported calculation of underestimation was that of Tylleskar²⁵ in the DRC in 1994, when he estimated that at least twice as many cases may have occurred as those reported. The underestimation in the DRC is likely to be much greater more recently, due to war and displacement. It was therefore decided to account for the uncertainty in the underreporting by applying an expansion factor ranging uniformly from 1 to 10 to the observed cases. The mean annual incidence rate was therefore estimated as 0.9/100,000 (0.04 to 1.8/100,000). Our estimate of the burden of konzo is restricted to the 5 African countries described above and Angola. The decision to include Angola is based on a report to the World Congress on Neurology suggesting that cases have occurred in that country²⁶. Although cassava consumption occurs in tropical areas throughout the world, the term konzo has only been used to describe cases in Africa. The incidence of konzo in other countries in Africa and other parts of the world is assumed to be zero.

We assumed the age of onset and gender distribution of these cases to be that observed by Tylleskar²⁵. The konzo case-fatality ratio is approximately 21% based on four studies^25,27–29. The age and gender distribution of fatal cases was assumed to be that of Tshala-Katumbay²⁷.

The onset of paraparesis in konzo is abrupt, usually within minutes or hours, with occasional progression during the first days of the illness. After that time, the paraparesis is non-progressive and permanent. As a result, duration is defined as lifelong for non-fatal cases. For fatal cases, it was assumed that death occurred one to seven years after onset, with a most likely value of three years after onset, following Banea et al.²⁸ and Tylleskar et al.³⁰.

There is no DW specifically for konzo. The WHO defined three severity levels for konzo: (1) Mild = able to walk without support; (2) Moderate = uses one or two sticks or crutches to walk; and (3) Severe = not able to walk²⁴. The Global Burden of Disease (GBD) 2010 DWs for mild, moderate, and severe motor impairment are 0.012, 0.076, and 0.377, respectively³¹. The distribution of konzo severity among 753 patients from nine different studies were mild (63%), moderate (27%) and severe (10%)^{27,28,30,32–37}. This distribution and the disability weights described above were used to assign a disability weight of 0.065 to konzo.

Peanut allergen

Prevalence data on peanut allergy were used to make estimates of incidence since allergy occurs early in life (< 5years) and is believed to be lifelong^38–42. All peanut allergy cases are assumed to be the result of eating peanuts or peanut products. In western countries, the prevalence of clinical peanut allergy in children is 0 to 1.8% of the population³⁸, corresponding to incidence rates of 0 to 22.6 per 100,000. Limited data exist on the mortality rate of peanut-induced anaphylaxis, but the majority of studies found similar rates, ranging from 0 to 0.006 deaths per 100,000 person-years³⁸. Incidence was estimated only for the WHO A level (high income) subregions; too few data exist to make estimates for other subregions³⁸. Several studies have reported that 63–66% of cases are male³⁸, but given the uncertainty in this number, the gender distribution was assumed to be equal for the burden of disease calculations. No DW exists for peanut allergy. Mullins et al.³⁹ reported that 52% of cases referred to a specialist allergy medical practice in Australia suffered from mild symptoms (skin and subcutaneous tissue involvement only), 42% from moderate symptoms (features suggestive of respiratory, cardiovascular or gastrointestinal involvement), and 6% from severe symptoms (cyanosis, hypotension, confusion, collapse, loss of consciousness, incontinence). We propose the DW for peanut allergy be a weighted average accounting for this severity distribution. GBD 2010 DWs³¹ for the health states defined in the category “Asthma: controlled” (DW=0.009) are considered applicable for mild and moderate cases (94%), and “Generic uncomplicated disease: anxiety about the diagnosis” (DW=0.054) for severe cases (6%), because anxiety is known to impact quality of life in food allergic patients⁴³, leading to a severity-weighted DW of 0.012 for clinically relevant peanut allergy. Unlike other childhood allergies such as cow’s milk and egg allergy, peanut allergy rarely resolves^44,45.

Aflatoxin

Aflatoxins are secondary metabolites of the fungi Aspergillus flavus and A. parasiticus, and less frequently other Aspergillus species such as A. nomius⁴⁶. These species can be found in maize, peanuts (groundnuts), oilseeds, and tree nuts in tropical and subtropical regions⁴⁶. It is believed that all aflatoxin exposure results from food consumption. We assumed a multiplicative model for the effects of aflatoxin exposure and hepatitis B virus (HBV) infection and estimated excess risk due to aflatoxin exposure as described by Liu and Wu⁴⁶. To account for differences in background rates between the study population from which the cancer potency factor was derived⁴⁷ and global populations, we estimated population attributable fractions (PAFs) by country, and applied them to HCC incidence and mortality based on^48,49. A Bayesian log-normal random effects model⁵⁰ was used to extrapolate available PAFs to countries without data. Age-specific incidence estimates were derived from a study in China comparing age-specific incidence of HCC in Qidong, a city in China with high aflatoxin exposure, and Beijing, a city with low aflatoxin exposure⁵¹. The YLD and YLL envelopes for HCC that are available from WHO were multiplied by the proportion of the burden due to aflatoxin. Thus no DW was directly involved in the calculation.

Dioxin

Dioxins are mainly byproducts of industrial processes, but can also result from natural phenomena such as volcanic eruptions and forest fires. More than 90% of human exposure to dioxins is through the food supply. The foods most often associated with dioxin contamination are meat, dairy products, fish, and shellfish⁵². Due to the bioaccumulation and lipophilic characteristics of dioxins, daily dietary exposure leads to accumulation of these compounds in human body fat. In adults this accumulation is thought to reach a constant level (i.e., a steady state). Consequently, the dioxin body burden, rather than the daily exposure, is taken as the dose metric for chronic toxicity risk and the assessment of dioxins^53–58. In this context the dioxin concentration in breast milk fat directly reflects the concentration in body fat^58–61.

Many national authorities have programs in place to monitor dioxin in the food supply and breast milk^61–63. Dioxin-induced prenatal and postnatal hypothyroidism and prenatally induced reduced sperm production have been found to be the most sensitive non-cancer toxic endpoints for dioxins. Estimates for dioxin-induced prenatal and postnatal hypothyroidism and reduced fertility due to disturbed sperm formation were based on an exposure assessment, toxicity assessment, and the comparison of both assessments^64,65. The exposure assessment is based on breast milk concentrations of dioxin from 50 countries⁶³. The toxicity assessment utilizes the benchmark dose (BMD) approach^66–68 in which the dose response of postnatal total thyroxine (TT; decrease of TT4 in adult blood), prenatal thyroid stimulating hormone (TSH; increase in TSH in neonatal blood), and sperm production (reduced concentration of sperm cells) is analyzed. The toxicity and exposure assessments are compared to derive the transgression of a dioxin induced decrease in TT4, decrease in sperm cell count and increase in TSH across a physiological threshold indicating a disease status (i.e., incidence of hypothyroidism or impaired fertility). Additional details of these assessments may be found in Zeilmaker et al.⁶⁹. The BMD analysis was performed on studies which served as the starting point for the derivation of a tolerable weekly intake (TWI)^54–57 or reference dose for dioxin (RfD)⁵⁸.

In a study of a mother-child cohort, Baccarelli et al. determined the relationship between maternal plasma dioxin concentration and TSH level⁷⁰. A BMD analysis of these data resulted in a population distribution of the maternal body burden of dioxin corresponding to an increased TSH level of 5 µU/mL in offspring, a level not to be exceeded in 3% of newborns in iodine-replete populations⁷¹.

Following administration of an acute oral dose to pregnant Long Evans rats on day 15 of gestation, Gray et al. measured the reduction in cauda epididymis sperm count in male offspring⁷². The resulting dose response data were used to calculate a BMD lower confidence limit (BMDL) and upper confidence limit (BMDU) dioxin body burden for various levels of reduction in sperm count. A WHO reference cut-off value for impaired fertility of 20 × 10⁶ sperm cells/mL was used to link toxicity (sperm count reduction) to a disease status (impaired fertility) (i.e., the calculation of the probability of a male being born with dioxin-impaired fertility)⁷³.

A BMD analysis of a National Toxicology Program (NTP) two year feeding study in rats was used to make estimates of dioxin-induced thyroid toxicity. The NTP study administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)⁷⁴ and 2,3,4,7,8-pentachlorodibenzofuran⁷⁵ for periods of 14, 31, and 53 weeks. The concentrations were converted to toxic equivalent quotients⁷⁶ to enable a combined analysis of both congeners. BMDL and BMDU body burdens for reduction in TT4 were calculated for each of the exposure periods. A distribution of TT4 in human blood has been reported by Aoki et al.⁷¹. The 5^th percentile of this distribution (65 nmol/L) was used as the cut-off for overt clinical hypothyroidism in adults.

The results of the BMD analyses and the breast milk concentrations for 50 countries were compared, taking account of possible differences between experimental animals and humans and among individual humans^64,65. This comparison provided country-specific estimates of the incidence of dioxin induced prenatal and postnatal hypothyroidism and impaired fertility. The estimates were extrapolated to other countries for which no breast milk concentrations were available by means of Bayesian random effects modeling⁵⁰.