Systematic review of the potential respiratory carcinogenicity of metallic nickel in humans

Figures & data

Table 1. Criteria for evaluating causation and the human relevance of experimental studies.

Aspect	Criteria
Causation	Consistency: Repeatability of key events and effects across species/study designs
	Magnitude: Large, considering type of effect, background prevalence, species, dose range, and exposure pattern
	Essentiality: Reversibility of effects if exposure is stopped or a key event prevented
	Specificity: Apical effect is likely to occur following key event
	Temporality: Observation of key events in a hypothesized order, before toxicity is apparent
	Exposure–Response: Key events observed at exposures below or similar to those associated with the adverse effect
	Biological Concordance: Proposed mode of action is consistent with current biological knowledge of the toxicological outcome
	Analogy: Proposed mode of action is consistent with what is known for other related chemicals with a well-defined mode of action
Human Relevance	Relevant groups and lifestages
	Comparative developmental processes and their relative timing
	Differences in ontogeny that affect dose metrics (e.g. placental or lactational transfer, key metabolic enzymes)
	Consequences of interaction of chemical with cells, tissues, and organs
	Magnitude of exposure differences for observation of key events or apical outcome

Adapted from Boobis et al. (2008), Meek et al. (2014), and NTP (2019).

Table 2. Confidence in the biological plausibility of a health outcome in humans based on experimental studies.

	Evidence for human relevance	Inadequate evidence for human relevance	No evidence for human relevance
Experimental study results support causation	High	Moderate	Inadequate
Inadequate evidence for causation from experimental studies	Inadequate	Inadequate	Inadequate
Experimental study results support no causation	High (not plausible)	Moderate (not plausible)	Inadequate

Table 3. Modified Bradford Hill aspects for evidence integration.

Aspect	Explanation
Consistency	Evidence is stronger if consistent effects are observed among studies of different designs, people, places, circumstances, and times
Strength of association	Large and precise risk estimates are less likely to be due to chance, bias, or other factors
Coherence	All of the known facts related to the observed association from the various evidence streams fit together in a logical manner
Biological plausibility	Evidence on the biological mechanism of an effect allows a scientifically defensible determination for causation
Biological gradient	Evidence is stronger when a well-characterized exposure-response relationship exists (e.g. disease risk increases with greater exposure intensity and/or duration)
Temporality	Exposure must precede the occurrence of disease
Specificity	Evidence is stronger when disease is specific to an exposure or exposure is specific to disease
Analogy	Evidence is stronger when a similar substance is an established causal factor for a similar effect
Experiment	"Natural experiments" can provide strong evidence when an intervention or cessation of exposure results in a change in disease risks

Adapted from the modified Bradford Hill aspects presented by US EPA (2015).

Figure 1. The experimental and epidemiology evidence are integrated together, using modified Bradford Hill aspects to aid in judgment of causality, with experimental evidence informing the aspects of coherence and biological plausibility. A four-tiered framework for causality is used to reach a causal conclusion. Adapted from Goodman et al. (2020).

Table 4. Criteria for reaching conclusions about causality.

Conclusion	Criteria
Causal	All modified Bradford Hill aspects are met, or most are met and there is a likely explanation for each that is not met
Suggestive	Some of the modified Bradford Hill aspects have inadequate information, and all other aspects are met or there is a likely explanation for each that is not met
Inadequate	Most or all modified Bradford Hill aspects have inadequate information or are not met and there is no likely explanation for each that is not met
Not causal	Evidence indicates no causal relationship based on modified Bradford Hill aspects not being met

Table 5. Study quality/risk of bias ratings for cohort studies evaluating metallic nickel exposure and respiratory cancer outcomes.

Study	Key criteria			Other quality criteria				Tier
	Can we be confident in the exposure characterization?	Can we be confident in the outcome assessment?	Did the study design or analysis account for important confounding variables?	Was the study subject to attrition bias?	Did the study employ appropriate statistical approaches?	Did the study assess the temporality of exposure and outcome?	Were all measured outcomes reported?
Cragle et al. (1984)	++	+	+ O-Ni	+	+	++	+	1
Egedahl and Collins (2009)	++	+	+ O-Ni	++	+	–	+	1
Huvinen and Pukkala (2013)	++	+	+ OC	++	+	+	+	1
Sorahan (2004)	++	+	+ SMK/OC	++	+	++	+	1
Moulin et al. (2000)	+	+	–	++	+	++	++	2
Arena et al. (1998)	++	+	–	++	++	–	+	2
Jakobsson et al. (1997)	++	++	–	++	+	++	+	2
Hansen et al. (1996)	––	+	+ OC	++	+	–	++	2
Enterline and Marsh (1982)	++	+	–	++	++	++	+	2
Sorahan and Williams (2005)	++	+	+ OC/O-Ni	++	+	+	+	1
Svartengren et al. (2017)	++	+	–	++	+	++	+	2
Westberg et al. (2017)	++	+	–	++	+	++	+	2
Marsh et al. (2017a)	++	+	+ SMK/OC	++	++	++	+	1
Morfeld et al. (2017)	++	+	+ OC	++	–	++	+	1
McElvenny et al. (2017)	++	+	–	++	++	++	++	2
Marsh et al. (2017b)	++	+	+ SMK/OC	++	++	++	+	1

++, Definitely low risk of bias; +, probably low risk of bias; –, probably high risk of bias; ––, definitely high risk of bias. Ratings of probably high and definitely high risk of bias are shaded gray; adjusted confounder groups (in addition to sociodemographic characteristics) are shown in the confounding column. OC: occupational co-exposure; O-Ni: other (nonmetallic) nickel; SMK: smoking.

Table 6. Results of metallic nickel and respiratory cancer cohort studies.

Study	N (metallic nickel exposed)	Effect measure	Confounding adjustment	Group	Exposure metric	Exposure level	Unit of measure	Outcome (cancer site)	Cases	Effect estimate	95% CI	p Value	Global P	Trend P
Cragle et al. (1984); ICNCM (1990)	813	SMR	SD/O-Ni	NA	Workers versus US white male population	NA	NA	Lung	9	0.54	0.25–1.03	NR
								Nasal	0	0	0–16.77	NR
								Larynx	0	0	0–5.12	NR
	NR			Workers with ≥15 years since first exposure	Duration of employment	<1	Years	Lung	0	0	NR	NR
						1–4			1	0.43	NR	NR
						<5			1	0.34	0.08–1.89	NR
						5–9			3	0.71	NR	NR
						10–14			0	0	NR	NR
						≥15			5	1.09	NR	NR
						≥5			8	0.91	0.39–1.79	NR
						Total			9	0.6	0.17–1.13	NR
Egedahl and Collins (2009)	718	SMR	SD/O-Ni	NA	Workers versus national population	NA	NA	Respiratory system	13	0.75	0.40–1.29	NR
								Bronchus and Lung	12	0.74	0.38–1.29	NR
Huvinen and Pukkala (2013)	703	SIR	SD/OC	>5 year employment, stainless steel melting	Workers versus local population	NA	NA	Lung	2	0.76	0.09–2.76	NR
								Nose	0	0	0.00–72.2	NR
Sorahan (2004)	1999	SMR	SD	NA	Workers versus national population	NA	NA	Nose and sinuses	0	0	NR	NR
								Larynx	1	0.51	0.01–2.85	NR
								Lung and bronchus	64	0.87	0.67–1.11	NR
				5–9 years since hire				Lung	3	0.71	0.15–2.07	NR
				10–19 years since hire					11	0.69	0.34–1.24	NR
				20–29 years since hire					19	0.75	0.45–1.17	NR
				≥30 year since hire					31	1.1	0.75–1.56	NR
		RR	SD/SMK	NA	Cumulative duration of employment	5–9	Years	Lung	24	1	NR	NR
						10–19			29	1.25	0.71–2.18	NR
						≥20			11	1.3	0.61–2.74	NR
						RR for trend			NA	1.16	0.81–1.65	NR		NR
Moulin et al. (2000)	4897	SMR	SD	NA	Workers versus local population	NA	NA	Lung	54	1.19	0.89–1.55	NR
	All workers: 33 exposed cases/ 93 exposed controls (Workers with smoking habits: 23 exposed cases/48 exposed controls)	OR	SD/OC	All workers	Exposure to nickel		NA		NA	0.72	0.32–1.62	NR		>0.2
			SD/SMK/OC	Workers with smoking habits					NA	0.67	0.23–1.95	NR		>0.2
			SD	All workers	Increasing exposure levels		Categorical		NA	1.13	NR	NR		>0.2
			SD/SMK	Workers with smoking habits					NA	0.99	NR	NR		>0.2
			SD	All workers	Duration of exposure		Years categorized		NA	1.13	NR	NR		>0.2
			SD/SMK	Workers with smoking habits					NA	1.02	NR	NR		>0.2
			SD	All workers	Frequency unweighted cumulative dose		Score categorized		NA	1.07	NR	NR		>0.2
			SD/SMK	Workers with smoking habits					NA	1.01	NR	NR		>0.2
			SD	All workers	Frequency weighted cumulative dose		Score categorized		NA	1.02	NR	NR		>0.2
			SD/SMK	Workers with smoking habits					NA	0.89	NR	NR		>0.2
Arena et al. (1998)	31 165	SMR	SD	White male	Workers versus national population	NA	NA	Respiratory system	858	1.11	1.03–1.18	NR
				Nonwhite male					82	1.06	0.84–1.32	NR
				Female					47	1.31	0.96–1.74	NR
				White male				Larynx	24	0.79	0.50–1.17	NR
				Nonwhite male					4	0.99	0.27–2.55	NR
				Female					1	1.27	0.03–7.09	NR
				White male				Bronchus–trachea–lung	831	1.13	1.05–1.21	NR
				Nonwhite male					78	1.08	0.85–1.34	NR
				Female					46	1.33	0.98–1.78	NR
				White male				All other respiratory sites	3	0.35	0.07–1.02	NR
				Nonwhite male					0	0	NR	NR
				Female					0	0	NR	NR
				All workers				Lung	955	1.13	1.06–1.21	NR
				White male	Workers versus local population	NA	NA	Respiratory system	858	1	0.94–1.07	NR
				Nonwhite male					82	0.82	0.66–1.01	NR
				Female					47	1.24	0.93–1.65	NR
				White male				Larynx	24	0.67	0.45–1.01	NR
				Nonwhite male					4	0.79	0.29–2.12	NR
				Female					1	1.17	0.16–8.40	NR
				White male				Bronchus–trachea–lung	831	1.02	0.96–1.10	NR
				Nonwhite male					78	0.82	0.66–1.03	NR
				Female					46	1.26	0.94–1.68	NR
				White male				All other respiratory sites	3	0.32	0.10–1.00	NR
				Nonwhite male					0	0	NR	NR
				Female					0	0	NR	NR
				All workers				Lung	955	1.01	0.95–1.08	NR
Jakobsson et al. (1997)	719	SIR	SD	NA	Workers versus local population	NA	NA	Sinonasal	0	0	0.0–8.0	NR
								Larynx	1	0.7	0.0–3.9	NR
								Primary lung	7	0.6	0.2–1.2	NR
Hansen et al. (1996)	521	SIR	SD/OC	NA	Workers versus national population	NA	NA	Respiratory system	11	1.57	0.78–2.81	NR
Enterline and Marsh (1982); ICNCM (1990)	1353	SMR	SD	Hired in 1947 or later (alloy production)	Workers versus national population	NA	NA	Nasal	0	0	0–17.57	NR
					Workers versus local population			Lung	19	0.98	0.59–1.53	NR
								Larynx	0	0	0–5.95	NR
	NR			Hired in 1947 or later, with ≥15 years since first exposure	Duration of employment	<1	Years	Lung	0	0	NR	NR
						1–4			5	1.23	NR	NR
						<5			5	1.23	0.40–2.87	NR
						5–9			2	1.32	NR	NR
						10–14			3	1.37	NR	NR
						15–19			5	1.33	NR	NR
						≥20			3	0.48	NR	NR
						≥5			13	0.95	0.51–1.62	NR
						Total			18	1.01	0.60–1.60	NR
Sorahan and Williams (2005)	219	SMR	SD/OC/O-Ni	Pellet and powder production (known to be exposed to metallic nickel)	Workers versus national population	NA	NA	Lung	9	1.71	0.78–3.25	NR
Svartengren et al. (2017)	3713	SIR	SD	NA	Workers versus national population	NA	NA	Larynx	5	1.9	0.62–4.44	≥0.05
								Bronchus and lung, primary	45	1.38	1.01–1.85	<0.05
								Trachea, bronchus, lung and pleura, primary	45	1.33	0.97–1.77	≥0.05
				Latency <20 years	Duration of employment	≤20	Years	Lung	11	1.67	0.83–2.99	≥0.05
						>20			1	0.82	0.02–4.55	≥0.05
				Latency ≥20 years		≤20			22	1.43	0.89–2.16	≥0.05
						>20			11	1.17	0.59–2.10	≥0.05
Westberg et al. (2017)	15 633	SMR	SD	Company C – hot rolls production	Dichotomized level (versus median)	≤ 0.01	mg/m^3	Lung	18	>1	NR	NS
						>0.01				>1	NR	NS
				NA	Workers versus national population	NA	NA	Larynx	6	1.51	0.55–3.28	≥0.05
								Lung, bronchus, trachea	298	1.68	1.50–1.89	< 0.001
				Latency <20 years	Duration of employment	≤1	Years	Lung	40	2.4	1.7–3.2	<0.001
						1.01–2			7	2.2	0.9–4.6	≥0.05
						2.01–5			10	2.3	1.1–4.2	<0.05
						5.01–10			4	0.7	0.2–1.9	≥0.05
						10.01–15			7	1.7	0.7–3.5	≥0.05
						15.01–20			2	0.7	0.1–2.6	≥0.05
						>20			0	0	NR	NR
				Latency ≥20 years		≤1			105	1.8	1.5–2.2	<0.001
						1.01–2			19	1.7	1.0–2.7	<0.05
						2.01–5			28	2.1	1.4–3.0	<0.001
						5.01–10			16	1.7	1.0–2.7	<0.05
						10.01–15			8	1.1	0.5–2.2	≥0.05
						15.01–20			14	1.8	1.0–3.0	<0.05
						>20			35	1.3	0.9–1.8	≥0.05
Marsh et al. (2017a)	7304	SMR	SD	NA	Workers versus national population	NA	NA	Respiratory system	105	0.98	0.80–1.19	≥0.05
								Larynx	3	0.94	0.19–2.73	≥0.05
								Bronchus, trachea, lung	102	0.99	0.81–1.20	≥0.05
					Workers versus local population			Respiratory system	105	0.96	0.79–1.17	≥0.05
								Larynx	3	0.99	0.20–2.88	≥0.05
								Bronchus, trachea, lung	102	0.97	0.79–1.18	≥0.05
			SD/SMK					Lung	NR	0.7	NR	NR
		RR	SD		Exposure duration (county adjusted)	<1	Years	Lung	29	1			0.077	0.043
						1–4			18	0.62	0.34–1.15	≥0.05
						5–19			23	0.45	0.24–0.83	<0.05
						20+			30	0.54	0.29–0.98	<0.05
					Cumulative exposure (worker type 1 and county adjusted)	>0–0.0032	mg/m^3-years		26	1			0.895	0.659
						0.0033–0.023			23	0.91	0.44–1.89	≥0.05
						0.024–0.084			25	0.91	0.38–2.16	≥0.05
						0.085+			26	1.1	0.46–2.67	≥0.05
					Average intensity of exposure (worker type 1 and county adjusted)	>0–0.0027	mg/m^3		14	1			0.398	0.324
						0.0028–0.0033			33	1.72	0.87–3.41	≥0.05
						0.0033–0.0071			18	1.7	0.81–3.57	≥0.05
						0.0072+			35	1.6	0.76–3.35	≥0.05
		RR	SD/OC	Long-term (1+ years) workers, plant adjusted	Exposure duration	<5	Years	Lung	18	1			0.469	0.479
						5–9			10	0.87	0.39–1.95	≥0.05
						10–19			13	0.54	0.25–1.19	≥0.05
						20+			30	0.8	0.42–1.52	≥0.05
					Cumulative exposure	>0–0.0032	mg/m^3-years		4	1			0.811	0.857
						0.0033–0.023			16	0.66	0.21–2.03	≥0.05
						0.024–0.084			25	0.64	0.21–1.94	≥0.05
						0.085+			26	0.78	0.26–2.40	≥0.05
					Average intensity of exposure	>0–0.0027	mg/m^3		10	1			0.351	0.143
						0.0028–0.0032			25	1.72	0.79–3.78	≥0.05
						0.0033–0.0071			18	1.95	0.87–4.39	≥0.05
						0.0072+			18	1.94	0.81–4.67	≥0.05
Morfeld et al. (2017)	6865	SMR	SD	NA	Workers versus national population	NA	NA	Bronchus, trachea, lung	45	0.93	0.68–1.25	NR
		HR	SD/OC	NA	Cumulative Exposure	1 unit increment	mg/m^3-years	Lung	NR	1.09	0.01–81.81	0.97
					Mean Concentration	1 unit increment	mg/m^3	Lung	NR	4.13E − 46	6.60E − 140 to 2.59E + 48	0.343
McElvenny et al. (2017)	1538	SMR	SD	NA	Workers versus national population	NA	NA	Respiratory system	19	0.81	0.52–1.27	NR
								Trachea, bronchus, and lung	19	0.85	0.54–1.34	NR
					Duration of employment	5–19	Years	Lung	11	1.72	0.95–3.11	NR
						≥20			8	0.91	0.15–1.92	NR
					Workers versus local population	NA	NA	Respiratory system	19	0.81	0.51–1.26	NR
								Trachea, bronchus, and lung	19	0.85	0.54–1.33	NR
Marsh et al. (2017b)	32 354	SMR	SD	Short-term (<1 year) workers	Workers versus local population	NA	NA	Respiratory system	182	1.42	1.22–1.64	<0.01
								Larynx	6	1.74	0.64–3.79	≥0.05
								Bronchus, trachea, lung combined or lung	172	1.42	1.21–1.65	<0.01
				Long-term (≥1 year) workers				Respiratory system	297	1.08	0.96–1.21	≥0.05
								Larynx	4	0.48	0.13–1.24	≥0.05
								Bronchus, trachea, lung combined or lung	287	1.1	0.97–1.23	≥0.05
				NA	Workers versus national population			Respiratory system	479	1.25	1.14–1.36	<0.01
					Workers versus local population					1.19	1.08–1.30	<0.01
					Workers versus national population			Larynx	10	0.88	0.42–1.62	≥0.05
					Workers versus local population					0.85	0.41–1.57	≥0.05
					Workers versus national population			Bronchus, trachea, lung	459	1.26	1.15–1.38	<0.01
					Workers versus local population					1.2	1.09–1.31	<0.01
		RR	SD	Long-term (≥1 year) workers	Exposure duration	0	Years	Lung	28	1			0.603	0.905
						>0–<5			75	0.96	0.60–1.53	NR
						5–9			35	0.75	0.44–1.28	NR
						10–19			66	0.82	0.50–1.34	NR
						20+			81	0.98	0.60–1.62	NR
						1 unit increment			NR	0.002^a	NR	0.742
					Cumulative nickel exposure	<0.0019	mg/m^3*years		35	1			0.498	0.305
						0.0019–0.0196			66	0.84	0.54–1.31	NR
						0.0197–0.0686			92	0.95	0.62–1.46	NR
						0.0687+			92	1.09	0.70–1.68	NR
						1 unit increment			NR	0.269^a	NR	0.685
					Average intensity of nickel exposure	0	mg/m^3		28	1			0.114	0.227
						>0–0.00319			133	0.78	0.49–1.23	NR
						0.0032+			124	1.01	0.64–1.58	NR
						1 unit increment			NR	2.78^a	NR	0.832
		RR (adjusted for smoking)	SD/SMK	Long-term (≥1 year) workers	Nickel exposure	Unexposed	NA	Lung	28	1
						Exposed			257	1.06	0.55–1.57	NR

CI: confidence interval; HR: hazard ratio; NA: not applicable; NR: not reported; NS: non-significant; OC: occupational co-exposure; O-Ni: other (nonmetallic) nickel; RR: relative risk; SIR: standardized incidence ratio; SMK: smoking; SMR: standardized mortality ratio.

^a Continuous form slope estimate.

Table 7. Study quality/risk of bias ratings for experimental animal studies evaluating metallic nickel exposure and respiratory cancer outcomes.

Study	Species/assay	Key criteria			Other quality criteria					Tier
		Can we be confident in the exposure characterization?	Can we be confident in the outcome assessment?	Does the study have an adequate number of animals to detect effects of exposure?	Was administered exposure level adequately randomized?	Were experimental conditions identical across study groups?	Were research personnel blinded to study group?	Were outcome data complete without attrition or exclusion from analysis?	Did the study employ appropriate statistical approaches?
Hueper (1958)	Wistar rats/inhalation	–	–	++	––	+	–	––	––	2
Hueper (1958)	Bethesda rats, mice, guinea pigs/ inhalation			––						3
Hueper and Payne (1962)	Rats/injection	–	–	––	––	+	–	––	––	3
Hueper and Payne (1962)	Rats/inhalation	––		++						2
Hueper and Payne (1962)	Hamsters/ inhalation			––						3
Pott et al. (1987)	Rats/intratracheal	–	–	––	–	+	–	–	––	3
Ivankovic et al. (1988)	Hamsters/ intratracheal	+	–	++	++	+	–	+	++	2
Muhle et al. (1992)	Hamsters/ intratracheal	+	+	––	+	+	–	+	–	2
Oller et al. (2008)	Rats/inhalation	++	++	++	++	++	–	++	++	1

++, Definitely low risk of bias; +, probably low risk of bias; -: probably high risk of bias; –: definitely high risk of bias. Ratings of probably high and definitely high risk of bias are shaded gray.

Figure 2. Effect estimates are SMRs or SIRs for each study (filled squares). If a study also reported an RR or HR with adjustment for important potential confounders, those are presented directly below the SMR or SIR for that study (unfilled squares). (a) Workers with ≥15 years since first exposure and ≥15 years of employment. (b) 95% confidence interval of effect estimate was calculated from the number of observed and expected deaths based on Fisher's exact test, as it was not reported by the study authors. (c) >5 years of employment, stainless steel melting. (d) ≥30 years since hire. (e) Adjusted for smoking. (f) ≥20 years of employment. (g) Hired in 1947 or later, with ≥15 years since first exposure. (h) Pellet and powder production. (i) Latency ≥20 years and >20 years of employment. (j) Long-term (≥1 year) workers. (k) Cumulative exposure ≥0.085 mg/m³-years. (l) Adjusted for occupational co-exposures. (m) Cumulative exposure per 1 mg/m³-years increment. HR: hazard ratio; RR: relative risk; SIR: standardized incidence ratio; SMR: standardized mortality ratio.

Figure 3. (a) White males. (b) Hired in 1947 or later (alloy production). (c) Long-term (≥1 year) workers. SIR: standardized incidence ratio; SMR: standardized mortality ratio.

Figure 4. (a) White males. (b) Long-term (≥1 year) workers. SIR: standardized incidence ratio; SMR: standardized mortality ratio.

Table 8. Results of experimental animal studies of metallic nickel respiratory carcinogenicity.

Study	Species/strain	Group size/sex	Exposure concentration	Respiratory tumors (statistically significant only)	Other tumors (statistically significant only)
Inhalation studies
Hueper (1958)	Rat/Wistar	50 F, 50 M	15 mg/m^3 (average)	None	None
	Rat/Bethesda black	60 F		None	None
	Mouse/C57 black	20 F		None	None
	Guinea pig/Strain 13	10 F, 32 M		None	None
Hueper and Payne (1962)	Rat/unspecified	60 F, 60 M	NR	None	None
	Hamster/unspecified	100 M		None	None
Oller et al. (2008)	Rat/Wistar	50 F, 50 M	0.1 mg/m^3	None	None
		50 F, 50 M	0.4 mg/m^3	None	Adrenal gland pheochromocytomas (males only); adrenal cortical adenomas and carcinomas combined (females only)
Intratracheal administration studies
Hueper and Payne (1962)	Rat/Bethesda black	20 F, 14 M	8 mg/animal	None	None
Pott et al. (1987)	Rat/Wistar	39 F	6 mg/animal	None^a	None
		32 F	9 mg/animal	None^a	None
Ivankovic et al. (1988)	Hamster/Syrian golden	50 F, 50 M	10 mg/animal	None	None
		50 F, 50 M	20 mg/animal	None	None
		50 F, 50 M	40 mg/animal	Fibrosarcoma or rhabdosarcoma in mediastinum, pleura, and cervix, combined	None
Muhle et al. (1992)	Hamster/Syrian golden	30 F, 30 M	9.6 mg/animal	None	None

F: female; M: male; NR: not reported.

^a The authors reported adenocarcinomas or squamous cell carcinomas in the lungs of 9/39 rats in the 6 mg dose group and 7/32 rats in the 9 mg dose group, but the statistical significance of these findings was not evaluated.

Table 9. Study quality/risk of bias ratings for in vitro studies evaluating metallic nickel genotoxicity.

Study	Key criteria			Other quality criteria					Tier
	Can we be confident in the exposure characterization?	Can we be confident in the outcome assessment?	Were appropriate control groups assessed concurrently?	Did the study have an adequate number of replicates per study group?	Were experimental conditions identical across study groups?	Were research personnel blinded to test group?	Were outcome data complete?	Did the study employ appropriate statistical approaches?
Paton and Allison (1972)	––	–	–	–	+	–	––	–	3
Costa et al. (1981a)	–	+	++	++	+	–	++	++	2
Costa et al. (1981b)	+	+	++	–	+	–	++	–	2
Hansen and Stern (1984)	–	++	–	++	+	–	––	––	2
Assad et al. (1999)	+	+	–	–	+	–	++	++	2
Magaye et al. (2014)	–	++	++	–	+	–	++	++	2
Magaye et al. (2016)	+	++	++	++	+	–	++	++	1
Latvala et al. (2016)	+	++	++	++	+	–	++	++	1
Buxton et al. (2020) Mutagenicity test	+	++	++	++	+	++	++	++	1
Buxton et al. (2020) Micronucleus assay	+	++	++	+	+	++	++	++	1

++, definitely low risk of bias; +, probably low risk of bias; –, probably high risk of bias; —, definitely high risk of bias. Ratings of probably high and definitely high risk of bias are shaded gray.

Table 10. Results of in vitro mechanistic studies evaluating metallic nickel genotoxicity.

Study	Cell line	Metallic nickel substance	Endpoint	Exposure concentration (μg/mL)	Exposure concentration (μg/cm^2)	Result	p Value for statistically significant results
Paton and Allison (1972)	Human leukocytes	Nickel powder	Chromosome aberrations	NR	NR	Negative
Costa et al. (1981a)	Primary Syrian hamster embryo cells	Nickel powder	Morphological transformation	5	2	Negative
				10	4	Negative
				20	8	Negative
Costa et al. (1981b)	Primary Syrian hamster embryo cells	Nickel powder	Morphological transformation	5	0.6	Negative
				10	1.3	Negative
				20	2.5	Negative
Hansen and Stern (1984)	BHK-21 baby hamster kidney cells	Nickel metal dust	Transformation	100	16	Negative
				200	32	Positive	NR
				400	64	Positive	NR
Assad et al. (1999)	Human peripheral blood lymphocytes	Nickel powder	DNA double-strand breaks in interphase chromatin	100,000	NR	Positive	p < 0.001
			DNA double-strand breaks in metaphase chromatin	100,000	NR	Positive	p < 0.001
Magaye et al. (2014)	JB6 P + neonatal mouse epidermal cell line	Nickel particles	Transformation	NR	1	Positive (weak)	p < 0.05
Magaye et al. (2016)	A549 human lung alveolar epithelial adenocarcinoma cell line	Nickel particles	DNA strand breaks	1	NR	Negative
				5	NR	Negative
				10	NR	Negative
				15	NR	Negative
				25	NR	Positive	p < 0.001
Latvala et al. (2016)	A549 human lung alveolar epithelial adenocarcinoma cell line	Nickel metal powder sample Ni-m1	DNA strand breaks	NR	20 (4 h)	Negative
				NR	20 (24 h)	Positive	p < 0.05
		Nickel metal powder sample Ni-m2		NR	20 (4 h)	Negative
				NR	20 (24 h)	Negative
Buxton et al. (2020)	V79 Chinese hamster lung fibroblast cells	Nickel metal powder	Mutagenicity, without metabolic activation	5.9	1	Positive^a	p < 0.05
				14.7	2.5	Negative
				29.4	5	Positive^a	p < 0.05
				58.7	10	Positive^a	p < 0.05
				146.8	25	Negative
			Mutagenicity, with metabolic activation	2.9	0.5	Negative
				5.9	1	Negative
				14.7	2.5	Positive^a	p < 0.05
				29.4	5	Negative
				58.7	10	Negative
			Micronucleus, without metabolic activation	35.2 (4 h)	6	Negative
				70.4 (4 h)	12	Negative
				105.7 (4 h)	18	Negative
				35.2 (24 h)	6	Negative
				70.4 (24 hr)	12	Negative
				105.7 (24 h)	18	Negative
			Micronucleus, with metabolic activation	17.6	3	Negative
				35.2	6	Negative
				70.4	12	Negative

DNA: deoxyribonucleic acid; NR: not reported. ^aResults were deemed negative by the authors because the mutant frequencies were within the historical control range.

Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, Schlatter J, Seed J, Vickers C. 2008. IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol. 38(2):87–96.

 PubMed Web of Science ®Google Scholar

Meek ME, Palermo CM, Bachman AN, North CM, Lewis RJ. 2014. Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J Appl Toxicol. 34(6):595–606.

 PubMed Web of Science ®Google Scholar

National Toxicology Program [NTP], Office of Health Assessment and Translation (OHAT). 2019. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration. 101p. March 4 [accessed 2019 March 18]. https://ntp.niehs.nih.gov/ntp/ohat/pubs/handbookmarch2019_508.pdf.

 Google Scholar

United States Environmental Protection Agency [US EPA]. 2015. Preamble to the Integrated Science Assessments. EPA/600/R-15/067. [accessed 2015 December 1]. http://www.epa.gov/isa.

 Google Scholar

Goodman JE, Prueitt RL, Harbison RD, Johnson GT. 2020. Systematically evaluating and integrating evidence in National Ambient Air Quality Standards (NAAQS) reviews. Glob Epidemiol. 2:1000019.

 Google Scholar

Cragle DL, Hollis DR, Newport TH. 1984. A retrospective cohort mortality study among workers occupationally exposed to metallic nickel powder at the Oak Ridge Gaseous Diffusion Plant. In: Sunderman FW, editor. IARC Scientific Publication No. 53. Nickel in the Human Environment: Proceedings of a Joint Symposium held at IARC, Lyon, France, 8–11 March 1983. Lyon: International Agency for Research on Cancer (IARC); p. 57–63.

 Google Scholar

Egedahl RD, Collins MJ. 2009. Vital status of Sherritt nickel refinery workers (1954–2003). In: Budac J, Fraser R, Mihaylov I, Papangelakis V, Robinson D, editors. Hydrometallurgy of Nickel and Cobalt: Proceedings of 39th Annual Hydrometallurgy Meeting held in in conjunction with the 48th Annual Conference of Metallurgists, Montreal, Canada. Montreal, Canada: Canadian Institute of Mining, Metallurgy and Petroleum; p. 689–699.

 Google Scholar

Huvinen M, Pukkala E. 2013. Cancer incidence among Finnish ferrochromium and stainless steel production workers in 1967–2011: a cohort study. BMJ Open. 3(11):e003819.

 PubMed Web of Science ®Google Scholar

Sorahan T. 2004. Mortality of workers at a plant manufacturing nickel alloys, 1958–2000. Occup Med (Lond). 54(1):28–34.

 PubMed Web of Science ®Google Scholar

Moulin JJ, Clavel T, Roy D, Dananche B, Marquis N, Fevotte J, Fontana JM. 2000. Risk of lung cancer in workers producing stainless steel and metallic alloys. Int Arch Occup Environ Health. 73(3):171–180.

 PubMed Web of Science ®Google Scholar

Arena VC, Sussman NB, Redmond CK, Costantino JP, Trauth JM. 1998. Using alternative comparison populations to assess occupation-related mortality risk. Results for the high nickel alloys workers cohort. J Occup Environ Med. 40(10):907–916.

 PubMed Web of Science ®Google Scholar

Jakobsson K, Mikoczy Z, Skerfving S. 1997. Deaths and tumours among workers grinding stainless steel: a follow up. Occup Environ Med. 54(11):825–829.

 PubMed Web of Science ®Google Scholar

Hansen KS, Lauritsen JM, Skytthe A. 1996. Cancer incidence among mild steel and stainless steel welders and other metal workers. Am J Ind Med. 30(4):373–382.

 PubMed Web of Science ®Google Scholar

Enterline PE, Marsh GM. 1982. Mortality among workers in a nickel refinery and alloy manufacturing plant in West Virginia. J Natl Cancer Inst. 68(6):925–933.

 PubMedGoogle Scholar

Sorahan T, Williams SP. 2005. Mortality of workers at a nickel carbonyl refinery, 1958–2000. Occup Environ Med. 62(2):80–85.

 PubMed Web of Science ®Google Scholar

Svartengren M, Bryngelsson IL, Marsh G, Buchanich J, Zimmerman S, Kennedy K, Esmen N, Westberg H. 2017. Cancer incidence among hardmetal production workers: the Swedish cohort. J Occup Environ Med. 59(12):e365–e373.

 PubMed Web of Science ®Google Scholar

Westberg H, Bryngelsson IL, Marsh G, Buchanich J, Zimmerman S, Kennedy K, Esmen N, Svartengren M. 2017. Mortality among hardmetal production workers: the Swedish cohort. J Occup Environ Med. 59(12):e263–e274.

 PubMed Web of Science ®Google Scholar

Marsh GM, Buchanich JM, Zimmerman S, Liu Y, Balmert LC, Esmen NA, Kennedy KJ. 2017a. Mortality among hardmetal production workers: US cohort and nested case–control studies. J Occup Environ Med. 59(12):e306–e326.

 PubMedGoogle Scholar

Morfeld P, Groß JV, Erren TC, Noll B, Yong M, Kennedy KJ, Esmen NA, Zimmerman SD, Buchanich JM, Marsh GM. 2017. Mortality among hardmetal production workers: German historical cohort study. J Occup Environ Med. 59(12):e288–e296.

 PubMed Web of Science ®Google Scholar

McElvenny DM, MacCalman LA, Sleeuwenhoek A, Davis A, Miller BG, Alexander C, Cowie H, Cherrie JW, Kennedy KJ, Esmen NA, et al. 2017. Mortality among hardmetal production workers: UK cohort and nested case-control studies. J Occup Environ Med. 59(12):e275–e281.

 PubMedGoogle Scholar

Marsh GM, Buchanich JM, Zimmerman S, Liu Y, Balmert LC, Graves J, Kennedy KJ, Esmen NA, Moshammer H, Morfeld P, et al. 2017b. Mortality among hardmetal production workers: pooled analysis of cohort data from an international investigation. J Occup Environ Med. 59(12):e342–e364.

 PubMed Web of Science ®Google Scholar

International Committee on Nickel Carcinogenesis in Man [ICNCM]. 1990. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health. 16(1):1–82.

 PubMed Web of Science ®Google Scholar

Hueper WC. 1958. Experimental studies in metal cancerigenesis: IX. Pulmonary lesions in guinea pigs and rats exposed to prolonged inhalation of powdered metallic nickel. AMA Arch Pathol. 65(6):600–607.

 PubMedGoogle Scholar

Hueper WC, Payne WW. 1962. Experimental studies in metal carcinogenesis. Chromium, nickel, iron, arsenic. Arch Environ Health. 5:445–462.

 PubMed Web of Science ®Google Scholar

Pott F, Ziem U, Reiffer FJ, Huth F, Ernst H, Mohr U. 1987. Carcinogenicity studies on fibres, metal compounds, and some other dusts in rats. Exp Pathol. 32(3):129–152.

 PubMedGoogle Scholar

Ivankovic S, Zeller WJ, Komitowski D, Elder L, Lehmann E, Froehlich N. 1988. Carcinogenesis of Nickel Alloys in the Hamster Following Intratracheal Administration. [English translation]. Dortmund, Germany: Publication of the Bundesanstalt für Arbeitsschutz; p. 105.

 Google Scholar

Muhle H, Bellman B, Takenaka S, Fuhst R, Mohr U, Pott F. 1992. Chronic effects of intratracheally instilled nickel-containing particles in hamsters. In: Nieboer E, Nriagu JO, editors. Nickel and human health: current perspectives. New York (NY): John Wiley and Sons, Inc.; p. 467–479.

 Google Scholar

Oller AR, Kirkpatrick DT, Radovsky A, Bates HK. 2008. Inhalation carcinogenicity study with nickel metal powder in Wistar rats. Toxicol Appl Pharmacol. 233(2):262–275.

 PubMed Web of Science ®Google Scholar

Paton GR, Allison AC. 1972. Chromosome damage in human cell cultures induced by metal salts. Mutat Res. 16(3):332–336.

 PubMedGoogle Scholar

Costa M, Abbracchio MP, Simmons-Hansen J. 1981a. Factors influencing the phagocytosis, neoplastic transformation, and cytotoxicity of particulate nickel compounds in tissue culture systems. Toxicol Appl Pharmacol. 60(2):313–323.

 PubMed Web of Science ®Google Scholar

Costa M, Simmons-Hansen J, Bedrossian CW, Bonura J, Caprioli RM. 1981b. Phagocytosis, cellular distribution, and carcinogenic activity of particulate nickel compounds in tissue culture. Cancer Res. 41(7):2868–2876.

 PubMed Web of Science ®Google Scholar

Hansen K, Stern RM. 1984. Toxicity and transformation potency of nickel compounds in BHK cells in vitro. In: Sunderman FW, editor. IARC Scientific Publication No. 53. Nickel in the Human Environment: Proceedings of a Joint Symposium held at IARC, Lyon, France, 8–11 March 1983. Lyon, France: International Agency for Research on Cancer (IARC); p. 193–200.

 Google Scholar

Assad M, Lemieux N, Rivard CH, Yahia LH. 1999. Comparative in vitro biocompatibility of nickel-titanium, pure nickel, pure titanium, and stainless steel: genotoxicity and atomic absorption evaluation. Biomed Mater Eng. 9(1):1–12.

 PubMed Web of Science ®Google Scholar

Magaye R, Zhou Q, Bowman L, Zou B, Mao G, Xu J, Castranova V, Zhao J, Ding M. 2014. Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells. PLoS One. 9(4):e92418.

 PubMed Web of Science ®Google Scholar

Magaye R, Gu Y, Wang Y, Su H, Zhou Q, Mao G, Shi H, Yue X, Zou B, Xu J, et al. 2016. In vitro and in vivo evaluation of the toxicities induced by metallic nickel nano and fine particles. J Mol Histol. 47(3):273–286.

 PubMed Web of Science ®Google Scholar

Latvala S, Hedberg J, Di Bucchianico S, Moller L, Wallinder IO, Elihn K, Karlsson HL. 2016. Nickel release, ROS generation and toxicity of Ni and NiO micro- and nanoparticles. PLoS One. 11(7):e0159684.

 PubMed Web of Science ®Google Scholar

Buxton S, Voges Y, Donath C, Oller A. 2020. Gene (HPRT) and chromosomal (MN) mutations of nickel metal powder in V79 Chinese hamster cells. Mutat Res. 819–820:111688.

 PubMed Web of Science ®Google Scholar