The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

Figures & data

Table 1 Cohorts from epidemiology studies of styrene.

Reference	Job/Exposure Category	Subjects (n)	Total Follow-up (person-years)	Period of Follow-up	Minimum Employment Duration	Employ- ment Duration (Years)	Exposure Duration (Years)	Average Exposure (ppm)	Cumulative Exposure (ppm-yr)	Employment Start Date	Time Since Hire/First Exposure (Years)	Hourly Employee	Co-Exposures/ Confounders Discussed in Study
Reinforced Plastic Industry (RP)
Kolstad et al. (1994, 1995). Workers from Denmark.	Exposed: Ever worked in company producing reinforced plastic Low: 1–49% of  employees in RP  production High: 50–100% of  employees in RP  production Unexposed: Never  worked in company  producing  reinforced plastic Exposure unknown	50,903	584,556	1970–1989	<1 ≥1	<1 ≥1				1964–1970 1971–1975 1976–1988 ≤1970 >1970	<10 ≥10
Kogevinas et al. (1993, 1994). Workers from Denmark, Finland, Italy, Norway, Sweden and the United Kingdom.	Laminators Unspecified tasks Other exposed jobs Unexposed	40,688	539,479	1945–1991 (varies by country)			<2 ≥2	<60 60–99 100–119 120–199 > 200	<75 75–199 200–499 ≥500		<10 10–19 ≥20		Peroxides Styrene oxide Acetone Methylene chloride Other  aromatic  hydrocarbons Fibers Dust
Wong et al. (1994). Workers in the US.	Open mold processing Mixing and closed mold processing Finishing operations Plant supports Maintenance and preparation Supervisory and professional	15,826	307,932	1948–1989	≥6 months	<1 1–1.9 2–4.9 5–9.9 ≥10 up to 1977	<1 1–1.9 2–4.9 5–9.9 ≥10 up to 1977		<10.0 10.0–29.9 30.0–99.9 ≥100.0		<10 10–19 ≥20
Ruder et al. (2004). Workers at two boat-building plants in the US.	High exposure: Fiber glass (TWA = 42.5 ppm) or lamination (TWA = 71.7 ppm) Low exposure: Never worked in high-exposure departments	5,204	135,588	1959–1998	>1 d	<1 >1							Fiberglass Solvents Wood dust Wood  finishing  agents
Styrene-Butadiene Rubber Industry (SBR)
McMichael et al. (1976). Male workers at a tire plant in the US (OH).	SBR Plant 15 other work areas	6,678	–	1964–1973	>10 yr (99%)	>2 >5							Gases or  liquids that  are  ingredients  for the  particular  synthetic  rubber  being  made
Sathiakumar et al. (2005). Male workers at 8 US and Canadian synthetic rubber plants.	Production (polymerization, coagulation, finishing) Maintenance (shop, field) Labor (production, maintenance) Laboratories Other	17,924	–	1944–1991 1992–1998 1944–1998	≥1 yr	<10 ≥10					<20 20–29 ≥30	Ever Never	1,3-Butadiene DMDTC Benzene
Polystyrene/Styrene Production Industry (PS)
Frentzel-Beyme et al. (1978). Workers at BASF Ludwigshafen, Germany.	All employees engaged in the manufacture of styrene or polystyrene	1,960	20,138	1931–1976	>1 month
Bond et al. (1992). Male workers at Dow Chemical plants in the US.	Styrene monomer and finishing Styrene-butadiene latex production Product research and development Polymerization, coloring, extrusion All styrene-based products cohort Workers unexposed to styrene Styrene/ethylbenzene only Mixed exposures to styrene, ethyl benzene, benzene, alkylbenzenes, acrylonitrile Extrusion fumes; indirect colorants; styrene, ethylbenzene, or acrylonitrile Extrusion fumes; direct colorants; styrene, ethylbenzene, or acrylonitrile Polymer dusts plus styrene/ethylbenzene Several other categories 1-4 ppm and ≥5 ppm (8-hour TWA).	2,904	89,825	1937–1986	≥1 yr	<1 1–4 ≥5							Ethylbenzene Alkylbenzene  compounds Benzene Acrylonitrile Polymer dusts Styrene  oligomers Mineral oil Direct  colorants Indirect  colorants
Hodgson and Jones (1985). Male workers at a plant in England.	Laboratory and manual workers (styrene production, polymerization, and processing) Manual workers with no specific occupational styrene exposure	622	8,654	1945–1978	≥1 yr					1945–1958 1959–1968 1969–1974			Acrylonitrile Pitch Polyvinyl  chloride  fumes Benzene Dyestuffs Antioxidants Polyolefins Ethylene Oxide
Nicholson et al. (1978). Male workers at a plant in the US (TX).	Production and polymerization Maintenance Utilities service	560	–	1960–1975	≥5 yr						10–19 20–29 ≥30		Benzene
Styrene Monitored Workers
Anttila et al. (1998). Male and female workers biologically monitored by the Finnish Institute of Occupational Health.	Workers monitored by Finnish Institute of Occupational Health	2,580	34,288	1973–1983	—						0–9 ≥10
Environmental Exposure
Loughlin et al. (1999). Former students of an Eastern TX high school, located adjacent to styrene manufacturing facilities.	Students attending high school adjacent to SBR facility	15,403	310,254	1963/4– 1992/3	≥3 consecutive months attendance in a school year	≤2 ≥3
Abbreviations used: ppm = parts per million; ppm-years = ppm per day x number of years exposed; TWA = time-weighted average; DMDTC = dimethyldithiocarbamate

Table 2 Leukemia cancer risk in styrene job/exposure categories.

Study	Job/Exposure Category	Observed	Risk Estimate^a	95% CI^b
Reinforced Plastic Industry (RPC)^c
Kolstad et al. (1994, 1995)	1-49% employees in reinforced plastics	28	1.15	0.77–1.67
	50–100% employees in reinforced plastics	14	1.38	0.75–2.32
	Total Reinforced plastics	42	1.22	0.88–1.65
	No reinforced plastics	13	0.86	0.46–1.47
	Production unclassified	6	2.37	0.87–5.16
Kogevinas et al. (1993, 1994)	Laminators	3	0.48	0.10–1.39
	Unspecified Tasks	16	1.4	0.79–2.28
	Other exposed Jobs	4	0.94	0.26–2.40
	Unexposed	4	0.99	0.27–2.54
	Total	28	1.04	0.69–1.50
Wong et al. (1994)^d	Open mold processing	1	0.9
	Mixing and closed mold processing	0	–
	Finishing operations	2	0.8
	Plant supports	1	0.56
	Maintenance and preparation	1	0.48
	Supervisory and professional	1	1.33
	Total	11^e	0.74	0.37–1.32
Ruder et al. (2004)	High Exposure	1	0.46^f	0.01–2.58
	Low Exposure	4	0.64^f	0.17–1.63
	Total	5	0.59^f	0.19–1.38
Styrene-Butadiene Rubber Industry (SBR)^c
Sathiakumar et al. (2005)	Production, polymerization	18	2.04	1.21–3.22
	Production, coagulation	10	2.31	1.11–4.25
	Production, finishing	19	1.56	0.94–2.44
	Maintenance, shop	4	0.93	0.25–2.38
	Maintenance, field	10	0.84	0.40–1.55
	Labor, production	4	1.23	0.34–3.15
	Labor, maintenance	15	2.03	1.14–3.35
	Laboratories	14	3.26	1.78–5.46
	Other operations	6	0.69	0.25–1.50
McMichael et al. (1976)^g	Compounding, mixing: cement mixing		1.3	1.0–1.8
	Extrusion, tread cementing		3.2	2.4–5.0
	Inspection, finishing, repair		3.7	2.8–5.3
	Synthetic plant		3.9	2.6–8.0
Polystyrene/Styrene Production Industry (PS)^c
Bond et al. (1992)^d	Styrene monomer and finishing	1	–^h
	Styrene-butadiene latex production	1	–^h
	Product research and development	1	–^h
	Polymerization, coloring, extrusion	6	1.65
	Total	9	1.18	0.54–2.24
Hodgson and Jones (1985)	Exposed workers	0	–
	Unexposed workers	0	–
	Total	1^f	–^h
Nicholson et al. (1978)	Total	1	1/0.79
Environmental Exposure^c
Loughlin et al. (1999)	Men	6	1.82	0.67–3.96
	Women	1	0.45	0.01–2.48
^a Risk estimates were reported as one of the following: standardized mortality ratio (SMR), standardized incidence ratio (SIR), relative risk (RR), or standardized risk ratio (SRR). Some values were divided by 100 for comparison.
^b95% CI = 95% confidence interval.
^cStatistically significant findings indicated in bold.
^dIf 95% CI was not provided, statistical significance was indicated in study.
^eThe total includes the entire study cohort, it is not the sum of all the observed cases by exposure category.
^fCompared to the US population. Similar results when compared to Washington state population.
^gMcMichael et al. (1976) calculated 99.9% CIs and did not report non-significant associations.
^hSMR not calculated by authors if observed <3.

Table 3 Leukemia cancer risk based on several styrene exposure measures.

Reinforced Plastic Industry (RP)^a
	Kolstad et al. (1994, 1995)				Kogevinas et al. (1993, 1994)				Wong et al. (1994)
	Category	Obs^b	SIR	95% CI	Category	Obs	SMR/RR	95% CI	Category	Obs	SMR^c,d
Employment Duration (Years)									<1	0	—
									1–1.9	3	1.04
									2–4.9	4	1.13
									5–9.9	3	1.23
									≥10	1	0.35
Exposure Duration (Years)					<1^e	7	0.85	0.34–1.75	<1	0	—
					≥1^e	16	1.15	0.66–1.87	1–1.9	3	1.04
					<2^e	14	1.13	0.62–1.89	2–4.9	4	1.11
					≥2^e	8	0.91	0.39–1.79	5–9.9	3	1.18
									≥10	1	0.39
Cumulative Exposure (ppm-yr)					<75	11	1		<10.0	1	0.29
					100–199	2	0.46	0.10–2.09	10.0–29.9	4	1.12
					200–499	3	0.69	0.19–2.53	30.0–99.9	3	0.72
					≥500	5	0.86	0.26–2.83	≥100.0	3	0.80
					ptrend		>0.52
Employment Start Date	1964–1970	30	1.54	1.04–2.19
	1971–1975	9	1.00	0.46–1.90
	1976–1988	3	0.51	0.11–1.50
Time Since Hire/First Exposure (Years)	<10	10	0.71	0.34–1.31		Table 3	(1994)		<10	5	1.11
	≥10	32	1.57	1.07–2.22	<10	5	0.52	0.17–1.22	10–19	4	0.68
					10–19	13	1.50	0.80–2.57	≥20	2	0.46
					≥20	4	1.36	0.37–3.47
						Table 4	(1994)
					<10	5	1
					10–19	12	3.01	0.90–10.08
					≥20	4	3.79	0.70–20.59
					ptrend		0.094
						Table 3	(1993)
					<10	7	0.70	0.28–1.45
					10–19	11	1.20	0.60–2.15
					≥20	5	1.63	0.53–3.81
Average Exposure (ppm)					<60	3	1
					60–99	4	1.58	0.32–7.79
					100–119	8	4.43	0.98–20.03
					120–199	3	1.36	0.22–8.48
					≥200	3	2.16	0.29–16.24
					ptrend		0.47
Styrene-Butadiene Rubber Industry (SBR)^a
	Sathiakumar et al. (2005)
	Category	Obs	SMR^d	95% CI
Period of Follow-up (Years)	1944–1991	51	1.16	0.86–1.53
	1992–1998	20	1.17	0.71–1.81
	1944–1998	71	1.16	0.91–1.47
Hourly Employee	Ever	63	1.23	0.94–1.57
	Never	8	0.82	0.35–1.61
Years Since Hire (ysh) and Years Worked (yrs)	<20 ysh, <10 yrs	4	0.57	0.16–1.46
	<20 ysh, 10+ yrs	6	1.36	0.50–2.96
	20–29 ysh, <10 yrs	4	0.98	0.27–2.51
	20–29 ysh, 10+ yrs	19	2.58	1.56–4.03
	30+ ysh, <10 yrs	10	1.13	0.54–2.07
	30+ ysh, 10+ yrs	20	1.02	0.62–1.58
Environmental Exposure
	Loughlin et al.(1999)
	Category	Obs	SMR	95% CI
High School Attendance (Years)	≤2	3	5.29	1.09–15.46
	≥3	3	1.10	0.23–3.21
^aStatistically significant findings indicated in bold.
^bAbbreviations used: Obs = observed cases; SIR = standardized incidence ratio; 95% CI = 95% confidence interval; SMR = standardized mortality ratio; RR = relative risk; ppm = parts per million; ppm-yr = ppm per day x number of years exposed
^cValues were divided by 100 for comparison.
^d95% CIs were not provided; statistical significance was indicated in study.
^eThe 1-year cutoff was used in the 1993 study; the 2-year cutoff was used in the 1994 study.