Updated Italian cohort data continues to confirm lack of mesothelioma risk in pooled cohort of international cosmetic talc miners and millers

Figures & data

Table 1. Most recent cohort studies included in an updated pooled analysis of pleural cancers/mesotheliomas associated with employment as a cosmetic talc miner or miller.

Study	Employment	Follow-up period	Location	Sample size	ICD version	Person-years	Reference population for expected deaths or incident cases	Observed mesotheliomas	Expected mesotheliomas reported by authors	Observed pleural cancers	Expected pleural cancers reported by authors	Combined expected cancers reported
Ciocan et al. (2022)	1946 to 1995	1 January 1946 to 31 January 2020	Italy	Miners = 1,184 Millers = 565	9	64,349.38	Regional and National^a	0	NA	0	2.8	2.8
Wergeland et al. (2017)	1944 to 1972	1 January 1953 to 31 December 2011	Norway	Miners = 94 Millers = 296	7	15,687	National^b	0	NA	0	0.6	0.6
Wild et al. (2002)	1945 to 1994	1 January 1945 to 31 December 1996	France	Miners and Millers = 1,070	8 and 9	28,849	Regional and National^c	0	0.3	NA	NA	0.3
	1972 to 1995	1 January 1973 to 31 December 1995	Austria	Miners and Millers = 542	8 and 9	9,469	Regional^d	0	0.1	NA	NA	0.1
Fordyce et al. (2019)	1930 to 1940 and 1970 to 1983	1 January 1940 to 31 December 2012	Vermont, USA	Miners and Millers = 427	5, 6, 7, 8, 9, and 10	17,170	Regional and National^e	1	0.34^f	NA	NA	0.34
Total				4,178		135,524.38		1	0.74	0	3.40	4.14

^aRegional death rates were used for the period 1970 to 2020; national rates were used for the period 1950 to 1969. Rates were not available for the period 1946 to 1949, for which 1950 to 1954 national rates were used. Similarly, rates for the period 2015 to 2017 were used for the period 2015 to 2020.

^bNational rates were used, as these were recorded in the same national cancer registry used to identify pleural cancer incident cases.

^cLocal (département de l’Ariège) and national mortality rates were used. Local mortality rates were only available since 1968.

^dRegional rates of the federal state of Styria were exclusively used.

^eBoth United States national rates and rates for the state of Vermont were used. However, in accordance with confidentiality and privacy restrictions, Fordyce et al. (2019) only reported SMRs using United States national rates.

^fBased on the mid-value estimate of the expected number of mesotheliomas for the Vermont cohort reported by Fordyce et al. (2019, 2020). The lower- (0.17) and upper-bound (0.6) values of the expected number of mesotheliomas for the Vermont cohort were included in a sensitivity analysis (Table 2). The total number of expected cancers would therefore be 3.97 or 4.40 if either the lower- or upper-bound estimates, respectively, for the Vermont cohort were used in the pooled analysis.

NA: Not Applicable; ICD: International Classification of Diseases; SMR: Standardized Mortality Ratio.

Table 2. Statistical power for SMR calculated after study completion and the probability estimate available from the observed data^a.

Expected number of pleural cancer/mesothelioma cases^b	SMR	90% CI^c	Minimum detectable relative risk (SMR > 1.00)
			1.5			2.0			2.5			3.0
			Power^d		Probability Estimate^f	Power^d		Probability Estimate^f	Power^d		Probability Estimate^f	Power^d		Probability Estimate^f
			Exact	Approx.^e		Exact	Approx.^e		Exact	Approx.^e		Exact	Approx.^e
3.97	0.252	(0.013, 1.19)	0.25	0.20	0.0180	0.54	0.43	0.0032	0.77	0.66	0.0005	0.91	0.83	0.00009
4.14	0.242	(0.012, 1.15)	0.18^g	0.21	0.0145	0.45^g	0.45	0.0024	0.71^g	0.68	0.0004	0.87^g	0.85	0.00005
4.40	0.227	(0.012, 1.08)	0.22	0.21	0.0103	0.52	0.47	0.0015	0.77	0.71	0.0002	0.91	0.87	0.00003

^aBased on one observed mesothelioma case from Fordyce et al. (2019).

^bBased on expected values previously provided by Wergeland et al. (2017) for the Norwegian cohort (0.6), by Wild et al. (2002) for the French (0.3) and Austrian (0.1) cohorts, by Fordyce et al. (2019, 2020) for the Vermont cohort (0.14, 0.34, 0.6), plus an updated value for the Italian cohort (2.8) from Ciocan et al. (2022).

^cThe 90% CI is shown as that relates to a one-sided significance level of 0.05 used to test H₀: SMR = 1.00 vs. H_A: SMR > 1.00.

^dStatistical power to detect SMR of interest with one-sided significance level of 0.05.

^eBased on the normal distribution-based approximation of Beaumont and Breslow (1981).

^fEstimate of the probability α that the true SMR is greater than the SMR of interest as evaluated by the upper (1 – 2α)% confidence limits from p-value function (Figure 1).

^gThis seemingly discrepant decrease in power with increasing expected number of mesothelioma cases stems from the use of the discrete Poisson probability distribution to calculate exact statistical power values (Marsh et al. 2019; Ierardi and Marsh 2020; Marsh and Ierardi 2020).

SMR: Standardized Mortality Ratio; CI: Confidence Interval.

Figure 1. Confidence interval function for SMR estimate = 0.242 derived from pooled cosmetic talc miner/miller cohort studies.

Table 3. Selected 100(1–2α)% confidence intervals from confidence interval function analysis, SMR point estimate = 1/4.14^a = 0.242.

α	2α	100(1 – 2α)%	LCL	UCL	Notes
0.08184	0.1637	83.63	0.020627	1.00	2α = p-value for 1-tail test of null hypothesis H0: SMR = 1.00
0.05000	0.1000	90.00	0.012390	1.15	Conventional 90% CI^b
0.02500	0.0500	95.00	0.006115	1.35	Conventional 95% CI
0.01449	0.0290	97.10	0.003524	1.50	UCL = SMR of interest 1.5
0.00500	0.0100	99.00	0.001211	1.79	Conventional 99% CI
0.00235	0.0047	99.53	0.000562	2.00	UCL = SMR of interest 2.0
0.00036	0.0007	99.93	0.000088	2.50	UCL = SMR of interest 2.5
0.00005	0.0001	99.99	0.000013	3.00	UCL = SMR of interest 3.0

^aBased on one observed mesothelioma case (Fordyce et al. 2019), the mid-value estimate of 0.34 expected mesothelioma cases (Fordyce et al. 2020), and 3.8 expected mesothelioma cases from four European cohorts.

^b90% confidence interval shown to reflect the one-tailed significance level of 0.05 used to test H₀: SMR = 1.00 vs. H_A: SMR > 1.00.

α: Probability that the true value of the SMR is greater than the SMR of interest based on observed SMR and its variance.

SMR: Standardized Mortality Ratio; CI: Confidence Interval; LCL: Lower Confidence Limit; UCL: Upper Confidence Limit.

Ciocan C, Pira E, Coggiola M, Franco N, Godono A, La Vecchia C, Negri E, Boffetta P. 2022. Mortality in the cohort of talc miners and millers from Val Chisone, Northern Italy: 74 years of follow-up. Env Res. 203:111865.

 PubMed Web of Science ®Google Scholar

Wergeland E, Gjertsen F, Vos L, Grimsrud TK. 2017. Cause-specific mortality and cancer morbidity in 390 male workers exposed to high purity talc, a six-decade follow-up. Am J Ind Med. 60(9):821–830.

 PubMed Web of Science ®Google Scholar

Wild P, Leodolter K, Refregier M, Schmidt H, Zidek T, Haidinger G. 2002. A cohort mortality and nested case-control study of French and Austrian talc workers. Occup Environ Med. 59(2):98–105.

 PubMed Web of Science ®Google Scholar

Fordyce TA, Leonhard MJ, Mowat FS, Moolgavkar SH. 2019. A 37-year update on mortality patterns in an expanded cohort of Vermont talc miners and millers. J Occup Environ Med. 61(11):916–923.

 PubMed Web of Science ®Google Scholar

Fordyce TA, Leonhard MJ, Mowat FS, Moolgavkar SH. 2020. Letter to the Editor: Egilman et. al.'s misrepresentation of the Fordyce et al. (2019) Vermont talc miners and millers cohort study update. J Occup Env Med. 62(1):e19–e21.

 PubMed Web of Science ®Google Scholar

Beaumont JJ, Breslow NE. 1981. Power considerations in epidemiologic studies of vinyl chloride workers. Am J Epidemiol. 114(5):725–734.

 PubMed Web of Science ®Google Scholar

Ierardi AM, Marsh GM. 2020. Absence of mesothelioma risk maintained in an expanded international cohort of cosmetic talc miners and millers. Inhal Toxicol. 32(6):257–264.

 PubMed Web of Science ®Google Scholar

Marsh GM, Ierardi AM. 2020. Confidence interval function analysis to evaluate the risk of mesothelioma among an expanded international cohort of cosmetic talc miners and millers. Regul Toxicol Pharmacol. 115:104696.

 PubMed Web of Science ®Google Scholar