Association between dietary 3-monochloropropane-1,2-diol esters (3-MCPDE) and renal cancer in Peninsular Malaysia: exposure assessment and matched case-control study

Figures & data

Table 1. Food categories analysed for 3-MCPDE occurrence.

Food categories (no. of samples)
Vegetable fats and oils (42)	Fast food (18)
Milk and milk products (16)	Local kuih-muih (30)
Confectionaries (53)	Fried /grilled cooked dishes (48)
Snacks (29)	Stewed/ boiled cooked dishes (15)

Table 2. Preparation of standard solutions.

CAL	Compound	CAS	Name	µg/mL	Solvent
I	PP-3-MCPD	51930-97-3	rac 1,2-bis-palmitoyl-3-chloropropanediol	55	anhydrous THF
II	PP-3-MCPD	51930-97-3	rac 1,2-bis-palmitoyl-3-chloropropanediol	5.5	anhydrous THF
IS	PP-3-MCPD-d5	1185057-55-9	rac 1,2-bis-palmitoyl-3-chloropropanediol-D5	20	anhydrous THF

Table 3. 3-MCPDE occurrence levels in Malaysian food items (by categories).

Food category	No. of sample	Total 3-MCPDE (mg/kg wet weight)*
		Median/mean	IQR/SD	Min	Max	Range
Vegetable fats and oils	42	1.91*	1.899	0.065	7.776	7.71
Margarine	23	2.50*	1.641	0.222	6.786
Mayonnaise	3	0.14		0.080	0.140
Shortening	4	3.53	4.183	2.702	7.776
Evaporated creamer	7	0.12*	0.037	0.065	0.174
Concentrated creamer	5	0.76*	0.347	0.411	1.214
Milk and milk products	16	0.31*	0.308	0.000	0.910	0.91
Evaporated milk	3	0.09*	0.091	0.000	0.182
Butter	13	0.36*	0.273	0.000	0.910
Confectionary	53	0.34*	0.358	0.000	1.450	1.45
Flavored biscuit	8	0.53*	0.343	0.195	1.190
Plain biscuit	6	0.45*	0.160	0.264	0.698
Bun	6	0.05*	0.054	0.000	0.125
Cake	13	0.13	0.600	0.000	1.450
Doughnut	3	0.41		0.260	1.010
Cheese tart	2	0.11*	0.158	0.000	0.224
Chocolate bar	7	0.00	0.000	0.000	0.096
Chocolate spread	8	0.51*	0.368	0.127	1.066
Snacks	29	0.45	0.558	0.052	3.200	3.15
Fried fish sausage (Keropok lekor)	3	0.08		0.060	0.160
Fried Fish Crackers (Keropok Ikan)	3	0.59		0.300	1.340
Murukku	5	0.94	1.401	0.576	3.200
Potato chips	5	0.37*	0.267	0.065	0.703
Chicken flavoured snack	4	0.19	0.340	0.073	0.516
Seafood flavoured snack	4	0.46*	0.183	0.257	0.703
Fruit/vegetable flavoured snack	5	0.36*	0.299	0.052	0.761
Local kuih-muih	30	0.68	0.41	0.08	1.9	1.86
Kuih denderam	3	1.27		0.49	1.49
Prawn fritter (Cucur udang)	3	0.68		0.43	1.94
Curry puff (Karipap)	3	0.73		0.43	1.04
Cakoi	3	0.76		0.42	0.94
Vadai (Kuih Vadai)	3	0.67		0.58	0.82
Banana fritters (Pisang goreng)	3	0.66		0.34	1.01
Fried spring rolls (Popia goreng)	3	0.73		0.51	0.76
Fried cempedak (Cempedak goreng)	3	0.37		0.35	0.6
Fried sweet potato (Keledek goreng)	3	0.35		0.25	0.48
Deep-fried banana balls (Cekodok pisang)	3	0.15		0.08	0.24
Cooked food (fried)	48	0.41	0.38	0.04	5.04	5.00
Fried rice (Nasi goreng)	3	0.72		0.39	0.87
Stir-fried flat rice noodle (Char-kuey-teow)	3	0.59		0.3	0.62
Fried rice noodle (Bihun goreng)	3	0.41		0.1	0.47
Fried wheat noodle (Mee goreng)	3	0.23		0.15	0.33
Fried Indian Mackerel (Ikan kembung)	3	0.24		0.04	0.33
Indian flatbread (Roti canai)	3	0.45		0.43	0.61
Fried anchovies (Ikan bilis goreng)	3	1.67		1.43	1.71
Butter Prawn (Udang mentega)	3	1.05		1.04	5.04
Fried beef (Daging lembu goreng)	3	0.84		0.35	0.99
Bergedil daging	3	0.46		0.43	0.47
Beef beriani (Daging beriani)	3	0.41		0.37	0.47
Beef murtabak (Murtabak daging)	3	0.16		0.09	0.17
Beef satay (Satay daging lembu)	3	0.24		0.21	0.35
Fried chicken (Ayam goreng)	3	0.06		0.06	0.51
Fried Macaroni (Makaroni goreng)	3	0.09		0.08	0.46
Fish Ball (Bebola ikan)	3	0.24		0.23	0.28
Fast food	18	0.16	0.17	0.06	0.46	0.40
Beef burger patty (Burger daging)	3	0.30		0.26	0.42
French fries (Kentang goreng)	3	0.14		0.1	0.46
Frankfurter/ sausage (sosej)	3	0.17		0.1	0.26
Nugget (Nuget)	3	0.20		0.11	0.23
Hot dog	3	0.11		0.07	0.11
Pizza with beef and onion	3	0.06		0.06	0.06
Cooked food (stewed/boiled)	15	0.18	0.4	0.02	1.05	1.03
Instant noodles (Mee segera)	3	0.18		0.16	0.49
Beef in soy sauce (Daging lembu masak kicap)	3	0.26		0.09	0.46
Chicken soto (Soto Ayam)	3	0.06		0.02	0.07
Beef curry (Kari daging lembu)	3	0.81		0.24	1.05
Satay sauce (Kuah satay)	3	0.06		0.06	0.08

Comparison of 3-MCPDE levels for different food groups (χ²_KW: 74.59, p = .001)

*Values are reported in mean with respective SD

Figure 1. 3-MCPDE occurrence level per food category (mg/kg). Box plots represent the median, interquartile range, minimum and maximum levels in selected food categories. FF: Fast food; CFT: Confectionary; CBS: Cooked (boiled/stewed); MM: Milk and milk products; SN: Snacks; CF: Cooked (fried); KM: Kuih-muih; FO: Fats and oils ^Ο Outlier values: more than 1.5 × IQR (Boiled/stewed food: Beef curry; Snacks: Murukku; Cooked fried food: Fried anchovies) * Extreme outlier value for evaporated milk: 0.09 ± 0.091 mg/kg.

Table 4. Sociodemographic distribution of study subjects.

Variable	Cases (N = 77)		Controls (N = 80)
	n	%	n	%	p-value
Age (years)
18–39	9	11.7%	10	12.5%	.974
40–59	34	44.2%	36	45.0%
>60	34	44.2%	34	42.5%
Race (ethnic)
Malay	31	40.3%	53	66.3%	.003
Chinese	33	42.9%	17	21.3%
Indian	9	11.7%	8	10.0%
Others	4	5.2%	2	2.5%
Gender
Male	48	62.3%	50	62.5%	.983
Female	29	37.7%	30	37.5%
Residence
Urban	38	49.4%	57	71.3%	.001
Sub-urban	28	36.4%	23	28.8%
Rural/village	11	14.3%	0	0.0%
Income level (per month)^a
4000–4999	6	7.8%	12	15.0%	.001
3000–3999	11	14.3%	15	18.8%
2000–2999	4	5.2%	13	16.3%
1000–1999	10	13.0%	15	18.8%
<1000	46	59.7%	25	31.3%
Education level
Primary school	17	22.1%	11	13.8%	.003
Secondary school	45	58.4%	34	42.5%
College	5	6.5%	14	17.5%
University	10	13.0%	21	26.3%

^aMYR: Malaysian Ringgit

Table 5. Measure of association for risk factors of renal cancer.

Risk factors	Cases (N = 77)	Controls (N = 80)	Unadjusted			Adjusted
	n (%)	n (%)	COR	95% CI	p-value	AOR	95% CI	p-value
Race
Malay (ref)	31 (40.3)	53 (66.3)
Chinese	33 (42.9)	17 (21.3)	3.32	1.59–6.91	**.001^**	5.15	2.21–12.01	**.001
Indian	9 (11.7)	8 (10.0)	1.92	0.67–5.50	.22	2.60	0.84–8.12	.10
Others	4 (5.2)	2 (2.4)	3.42	0.59–19.76	.17	5.08	0.89–31.91	.08
BMI
Normal (ref)	36 (46.8)	31 (39.2)
Underweight	7 (9.1)	4 (5.1)	0.64	0.17–2.41	.51	1.36	0.34–5.48	.67
Overweight	19 (24.7)	30 (38.0)	0.36	0.09–1.4	.14	0.59	0.25–1.36	.21
Obese	15 (19.5)	14 (17.7)	0.61	0.15–2.55	.50	1.08	0.41–2.81	.88
Hazard* exposure
Non-exposed (ref)	64 (83.1)	70 (87.5)
Exposure to hazard*	13 (17.9)	10 (12.5)	1.42	0.58–3.47	.44	1.02	0.37–2.79	.98
Family history of cancer
No family history (ref)	43 (55.8)	49 (61.3)
With family history	34 (44.2)	31 (38.8)	1.25	0.66–2.36	.49	1.24	0.61–2.52	.55
Both first, second degree	4 (5.2)	8 (10.0)	0.57	0.16–2.03	.39	0.39	0.09–1.53	.18
First degree only	16 (20.8)	14 (17.5)	1.3	0.57–2.97	.53	1.13	0.44–2.85	.81
Second degree (only)	14 (18.2)	9 (11.3)	1.77	0.69–4.50	.23	2.29	0.83–6.28	.11
Cigarette smoking
Never smoked (ref)	41 (53.2)	52 (65.0)
Former/ Current Smoker	36 (46.8)	28 (35.0)	1.63	0.86–3.10	.13	1.71	0.73–3.10	.22
1–20 pack years	23 (29.9)	19 (23.8)	1.57	0.75–3.25	.23	1.47	0.64–3.38	.37
More than 20 pack years	13 (16.9)	8 (10.0)	2.1	0.79–5.54	.13	1.48	0.49–4.45	.49
Fried food intake frequency
1–3 times monthly (ref)	5 (6.5)	3 (3.8)
1–3 times weekly	34 (44.2)	47 (58.8)	0.43	0.10–1.94	.28	0.47	0.09–2.30	.35
Once daily	23 (29.9)	20 (25.0)	0.69	0.15–3.26	.64	1.35	0.25–7.35	.73
Twice or more daily	15 (19.5)	10 (12.4)	0.9	0.18–4.64	.90	1.70	0.29–10.01	.56

COR: crude odds ratio; AOR: adjusted odds ratio, adjusted for age, gender, and all risk factors above.

*Hazard: chronically exposed for more than 5 years to toxic chemicals/radiation/polluted air (further defined under Appendix 1: Variable definitions).

^** Values with <0.05 significance level.

Figure 2. Graphic representation comparing the mean estimated daily intake (mg/day) of 3-MCPDE according to (A) group (case/control) and (B) ethnicity with 95% CI (T-Bar).

Table 6. Comparison of total EDI and individual EDI of 3-MCPDE (case and control group).

Variable	N	Total EDI	EDI*	IQR	Range		p value
		(mg/day)	(mg/day/person)		Min	Max
Cases	77	16.449	0.115	0.137	0.010	3.213	.405
Controls	80	15.487	0.105	0.151	0.002	3.256
Total subjects	157	31.936	0.111	0.143	0.002	3.256

EDI: estimated daily intake per person for each group (median ± IQR).

Table 7. Comparison of EDI (mg/day/person) of 3-MCPDE between groups considering ethnicity and gender.

Gender	Cases					Controls					Total
	n	Median EDI	IQR	Range		n	Median EDI	IQR	Range		n	Median EDI	IQR	p value
				Min	Max				Min	Max
Malay
M	14	0.204	0.382	0.059	3.213	32	0.160	0.223	0.025	3.256	84	0.162	0.229	.13
F	17	0.204	0.168	0.046	0.434	21	0.111	0.157	0.029	0.54
Chinese
M	27	0.109	0.121	0.009	0.319	12	0.079	0.111	0.018	0.207	50	0.098	0.092	<.001
F	6	0.097	0.071	0.02	0.114	5	0.042	0.089	0.002	0.123
Indian
M	6	0.202	0.207	0.067	0.344	5	0.207	0.351	0.052	0.501	17	0.085	0.204	.64
F	3	0.078		0.056	0.08	3	0.026		0.002	0.052
Others
M	2	0.134		0.063	0.205	1	0.026^a				6	0.054	0.103	.07
F	2	0.077		0.046	0.107	1	0.029^a

Comparison of EDI between case and control group of different ethnicity and gender: χ² _KW = 20.35, p = .001. M: Male; F: Female; EDI: estimated daily intake per participant (median ± IQR).

^aActual value reported, as frequency is one per group

Appendix 1. Variable definitions.

Age	Categorised based on current age at the time of interview Age group 1 : ≥ 18–39 Age group 2 : 40–59 Age group 3 : 60 years old and above.
Body mass index (BMI)	Classification based on the World Health Organization (1998) classification (WHO, 2000) Underweight <18.5 kg/m^2 Normal   = 18.5–24.9 kg/m^2 Overweight = 25–29.9 kg/m^2 Obese    ≥30 kg/m^2
Household income	Categorised based on average household income following the reporting of household income group from the National Health and Morbidity Survey (NHMS) (Institute for Public Health (IPH) 2015).
Education level	Primary Education: Standards 1–6 Secondary Education: Form 1 to Form 5 College: Matriculation, Certificate, Diploma University: Bachelor Degree, Master’s degree, Doctorate
Hazard exposure	Exposed: Individual chronically exposed for more than 5 years before diagnosis (for cases) and before the interview (for controls) to any of the following: Toxic chemicals – include gases (formaldehyde etc.), liquids (benzene, mineral oils, metal working fluids, hair dyes etc.), solids (wood dust, silica dust, asbestos, lead, arsenic etc.), fumes (welding fumes, coal tar fumes etc.), and solvents (International Agency for Research on Cancer (International Agency for Research on Cancer (IARC) 2012). Radiation – ionizing radiation (X-rays, radon etc.), ultraviolet radiation (solar radiation, artificial sources such as welding), artificial optical radiation (sunbeds, sunlamps, and fluorescent lamps) (Dayan 1993) Pollutants – include air pollution and fine particulate matter (emissions from motor vehicles, industrial processes, power generation, and other sources polluting the ambient air) (International Agency for Research on Cancer (IARC), 2016). Non-exposed: individuals not exposed to any of the above
Family history	Having history of diagnosed kidney cancer within the family. First degree: biological parents, siblings, children Second degree: grandparents, grandchildren, uncles, aunts, cousins, nephews, nieces
Cigarette smoking	Never smoked : An individual who had never smoked or had smoked <100 cigarettes in his lifetime Former/current smoker: Individuals who had smoked at least 100 cigarettes in his lifetime but had quit at least 12 months before diagnosis (for cases) or before the interview (for controls) were classified as a former smoker. Current smokers were those who were currently smoking or quit <12 months before diagnosis (for cases) or before the interview (for controls). Formula for calculation of pack years: $\text{Pack years}=\frac{\begin{array}{c} \mathit{Average} \mathit{number} of\\ \mathit{cigarettes} \mathit{per} \mathit{day}\end{array}}{20} \times \text{smoking years}$

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