Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases

Figures & data

TABLE 1A. Dose-Effect Relationship of Asbestos-Induced Mutagenic/Carcinogenic Responses—DNA Alterations

Reference	Study type	Assay system	Assay endpoints	Dose-response shape	Limit dose with response (significant?)	Limit significant (or dose)	Lowest effective dose^#	Type of assay*
(Cleveland, 1984)	Cells Prokaryote	Escherichia coli	Richterite (analogue of tremolite) Ames test w/wo rat liver homogenates (S9)	Not done	Mutations w/wo S9, 0.01g/plate		(0.01g/plate)^3	DNA bacteria
(Faux et al., 1994)	Cells Prokaryote	S. typhimurium TA 102	UICC Ch, Cr: 5–500 μg/plate mutagenicity	Dose-effect	Cr = 10 μg/plateCh = no effect		(10 μg/plate)^3	DNA Bacteria
(Howden and Faux, 1996a)	Cells Prokaryote	S. typhimurium TA 104	UICC Ch: 0.4 mg, UICC Cr: 0.4, 0.8 mg—DNA adducts	Not done (1 dose)		Ch, Cr : 0.4 mg	(0.4 mg)^1	DNA Bacteria
(Bertino et al., 2007)	Cells	Human normal mesothelial	UICC : B Ch, Am : (a) cytotoxicity : 1–10 μg/cm^2, (b) DNA synthesis : 0.5–10 μg/cm^2, (c) DNA adducts: 8-OH-dG (with AM 10 μg/cm^2), apoptosis, signaling, transformation (focus assay)	Dose-effect (a) plateau	(a) 1 μg/cm^2 no transformation	(c) 8-OH-dG / 10 μg/cm^2	(10 μg/cm^2)^1 (10 μg/cm^2)^4	DNA
(Blake et al., 2007)	Cells	Mouse macrophages, MM; RAW264.7 cells; primary alveolar macrophages lavaged from C57BL/6 mice (PAM)	Libby amphibole fibers (6-mix), Cr (RTI, NC) (a) internalization 5 μg/cm^2 (b) ROS production 6.25–62.5 μg/cm^2 (c) 8-oxo-dG and DSBs (comet)	Not done (a) Dose-effect (b) Not done (c)	(a) 5 μg/cm^2 S6 mix uptake in RAW264.7 (c) 8-oxo-dG and DSBs, in RAW264.7: 62.5 μg/cm^2 Cr; 62.5 μg/cm^2 S6 mix n.s.	(b) 6.25 μg/cm^2 S6 mix in RAW264.7	(62.5 μg/cm^2)^1	DNA
(Cavallo et al., 2004)	Cells	MeT-5A	NIEHS Cr: 1, 2, 5, 10 μg/cm^2 (Comet ± Fpg)	Dose-effect (+ Fpg) = oxidative)- plateau		1 μg/cm^2	(1.0 μg/cm^2)^1	DNA
(Chao et al., 1996)	Cells	A549 human epithelial	Cr: 1.5, 3, 6 μg/cm^2 (a) cytotoxicity, (b) NO production, (c) 8OH-dG in DNA	Not done (≈ plateau, cytox—linear n = 3)	(a) 1.5 μg/cm^2 (b) Concentration not provided	(c) 1.5 μg/cm^2	(1.5 μg/cm^2)^1	DNA
(Denizeau et al., 1985b)	Cells	Hepatocytes	UICCB Ch: 10, 100 μg/ml—UDS	No effect— linear negative slope (toxicity)			(100 μg/ml)^4	DNA
(Denizeau et al., 1985a).	Cells	Hepatocytes	UICCB Ch: 10 μg/ml—UDS	No effect (1 point)			(10 μg/ml)^4	DNA
(Dong et al., 1994)	Cells	Rat pleural meso	UICC: A Ch, Cr(a) cytotoxicity: 2, 5, 10, 20, 40 μg/cm^2; (b) proliferation: 2, 4, 10, 10 μg/cm^2; (c) UDS: 2, 4, 10, 10 μg/cm^2	(a) ≈ plateau(b) Not done(c) Not done	(a) 2 μg/cm^2	(b) 2 μg/cm^2 (c) Ch = 2 μg/cm^2; Cr = 4 μg/cm^2	[2 μg/cm^2 (Ch)]^1 [2 μg/cm^2 (Cr)]^2	DNA
(Dong et al., 1995)	Cells	Rat pleural meso	UICC: A Ch, Cr(a) cytotoxicity: 0, 2, 5, 20, 40 μg/cm^2— (b) poly(ADP-ribose) synthesis: 0, 2, 5, 20, 40 μg/cm^2	(b) Ch: ≈ polynomial order 3; Cr: linear up to 20 μg/cm^2, then plateau	(b) 2 μg/cm^2		(2 μg/cm^2)^3	DNA
(Howden et al., 1996a)	Cells	RFL-6	UICC Ch: 5 μg/cm^2, UICC Cr: 2, 5 μg/cm^2 DNA adducts	Not done (1 or 2 doses)	Ch: low effect at 5 μg/cm^2	Cr: 5 μg/cm^2	(5 μg/cm^2)^3	DNA
(Kamp et al., 1995)	Cells	WI-26 (SV40-transformed human embryonal lung)	UICC Ch, Am— (a) cytotoxicity: 250 μg/cm^2 (or 500 μg/ml)— (b) .OH production: 0.5–500 μg/cm^2— (c) DNA-SB (alkaline unwiding): 0.25, 2.5, 25 μg/cm^2	Not done AmOne dose Ch	(a) Am: no effect	(b) Am: 50 μg/cm^2— (c) Am: 0.25 μg/cm^2 (72 h of treatment); Ch: 25 μg/cm^2	(0.25 μg/cm^2)^1	DNA
(Kamp et al., 1995)	Cells	A549 (human bronchoalveolar carcinoma-derived) Rat alveolar epithelial	UICC Am: DNA-SB (alkaline unwiding); 25, 250 μg/cm^2	Not done (2 points)		25 μg/cm^2 in both cell types	(0.25 μg/cm^2)^1	DNA
(Kim et al., 2001)	Cells	A549 human epithelial	UICC Cr: 10, 50, 100 μg/ml (in 6 well plates)— (a) 8-OH-dG— (b) OGG1 activity	Not done	(b) 100 μg/ml (one dose)	(a) 50 μg/ml no effect at 10 μg/ml	(50 μg/cm^2)^3	DNA
(Levresse et al., 2000)	Cells	Rat pleural meso	UICC A Ch: 0, 0.5, 2, 5, 10 μg/cm^2; Cr: 0, 2, 10 μg/cm^2 Comet assay (tail length, MTM)	Dose response ≈ linear or log		Ch: 0.5 μg/cm^2 Cr: 10 μg/cm^2	(0.5 μg/cm^2)^1	DNA
(Libbus et al., 1989)	Cells	Rat embryo cells	UICC Cr: 2 μg/cm^2— (a) DNA strand breaks (nick translation, morphology); (b) cell proliferation (^3HdThd incorporation)	(a) Not done (1 dose) (b) log	(b) 0.5 μg/cm^2	(a) 2 μg/cm^2	(2 μg/cm^2)^1	DNA
(Liu et al., 2000)	Cells	Rabbit pleural mesothelial	NIEHS Cr: 10 μg/cm^2—DNA breakage	Not done		10 μg/cm^2	(10 μg/cm^2)^3	DNA
(Msiska et al., 2009)	Cells	Normal human small airway epithelial (SAE) human bronchial epithelial cancer (A549)	Cr NIEHS: 100 μg/ml— (a) cytotoxicity, (b) ROS production, (c) DNA DSBs: γHzAZfoci H2AX ^ion, (d) apoptosis: caspase 3/7 activation, (e) pARP induction if medium equivalent to 5 ml for 25 cm^2 as in flasks ≤ ∼20 μg/cm^2	Not done	(b) 0.5 μg/cm^2	(a) 100 μg/ml: SAE cells— (b) 100 μg/ml: A549 & SAE— (c) 100 μg/ml: A549 & SAE— (d) 100 μg/ml: SAE	(100 μg/ml)^1	DNA
(Murata-Kamiya et al., 1997)	Cells	J774 sarcoma cell line	UICC Ch, Cr, Am: 8-OH-dG (HPLC)	Dose-effect— ≈ linear (Cr) not done (1 dose) other fibers	Ch: n.s. at 100 μg/ml (1 dose)	Cr: ≈ 10 μg/mlAm: 100 μg/ml (1 dose)	(10 μg/ml)^1 (100 μg/ml)^3	DNA
(Okayasu et al., 1999a)	Cells	CHO and xrs-5 (DSB-repair deficient)	UICC A Ch 0, 8, 16 μg/cm^2—DSB	Dose-effect— ≈ linear in both cell types; enhanced in xrs-5/CHO		8 μg/cm^2	(8 μg/cm^2)^1	DNA
(Ollikainen et al., 1999)	Cells	Human TagSV40 mesothelial (MeT-5A)	UICC Cr(a) cytotoxicity: 1, 2 μg/cm^2, (b) DNA breakage (comet): 1, 2, 4 μg/cm^2, (c) ROS production: 1, 2 μg/cm^2	Not done (a)	(a) Not toxic(c) No effect	(b) 1 μg/cm^2	(1 μg/cm^2)^1	DNA
(Ollikainen et al., 2000)	Cells	A549 and MeT-5A	DNA breakage (comet): A549 = 2, 10 μg/cm^2; MeT-5A = 2, 4 μg/cm^2	Not done (2 doses)	2 μg/cm^2		(2 μg/cm^2)^3	DNA
(Pietruska and Kane 2007)	Cells	Murine mesothelial cell lines D9, D7—malignant mesothelioma cell lines, MeT-5A	UICC Cr—10 μg/cm^2— DSBs (γ-H2AX foci formation)—micronuclei—senescence	Not done		10 μg/cm^2; all tests	(10 μg/cm^2)^1	DNA
(Puhakka et al., 2002)	Cells	A549 and MeT-5A	UICC Cr: 2, 4 μg/cm^2—Comet (tail extent moment)	Not done (1 or 2 doses)		2 μg/cm^2	(2 μg/cm^2)^1	DNA
(Takeuchi and Morimoto, 1994)	Cells	HL60 (human promyelocytic leukemia cell line)	Cr: 15, 50, 150 μg/ml	Linear	15 μg/ml		(15 μg/ml)^3	DNA
(Turver and Brown 1987)	Cells	C3H10T1/2	UICC Cr 25–200 μg/cm^2—DNA-SB	Dose-effect— ≈ linear		25 μg/cm^2	(25 μg/cm^2)^1	DNA
(Topinka et al., 2004)	Cells ex vivo	Alveolar macrophages and type II from Big Blue	Am I.tr.: (a) 1, 2 mg; (b) 4 × 2 mg— (a) DNA-SB (comet); (b) micronucleus	(a) Dose-effect— ≈ log		(a) 2 mg in both cell types(b) 2 mg in macrophages; n.s. in type II	(2 mg)^1	DNA
(Xu et al., 1999)	Cells	AL cells	UICC Cr(a) nonprotein sulfhydryl (NPSH) depletion; 4 μg/cm^2 (b) 80H-dG staining; 2–12 μg/cm^2			(b) 4 μg/cm^2	(4 μg/cm^2)^3	DNA
(Jiang et al., 2008).	Animal	Rats	UICC: A Ch, Cr, Amosite (Am): 10 mg8OH-dG	Not done	10 mg: higher level with all fibers		(5 mg/ml)^3	DNA in vivo
(Jung et al., 2000)	Animal	Rats Sprague-Dawley	UICC Am: Itr 2.5 mg—DNA breaks in bronchiolar epithelial cells	Not done (1 dose)		2.5 mg	(2.5 mg)^3	DNA in vivo
(Unfried et al., 2002)	Animal	Transgenic F344 lacI rats (Big Blue)	UICC Cr: analysis of the greater omentum: (a) mutations: 2, 5 mg; (b) 8-OH-dG: 1, 2 mg	Not done (2 doses)	(a) 5 mg(b) 1 mg		(1 mg)^3	DNA
Note. #, Lowest effective dose: 1, sLOAEL: Surrogate lowest-observed-adverse-effect level. 2, sNOAEL: Surrogate no-observed-adverse-effect level. 3, pLOAEL: Potential lowest-observed-adverse-effect level. 4, pNOAEL: Potential no-observed-adverse-effect level. *Type of assay. “DNA” = 8-OH-dG, breaks, repair. DSB: Double Strand break

TABLE 1B. Dose-Effect Relationship of Asbestos-Induced Mutagenic/Carcinogenic Responses—Chromosomal Changes

Reference	Study type	Assay system	Assay endpoints	Dose-response shape	Limit dose with response (significant?)	Limit significant (or dose)	Lowest effective dose^#	Type of assay*
(Achard et al., 1987)	Cells	Cells rat pleural meso	Cr 10, 15, 20 μg/cm^2; SCEs	Dose-effect— ≈ linear (in highest dose)		10 μg/cm^2	(10 μg/cm^2)^1	CA
(Ault et al., 1995)	Cells	newt Taricha granulosa lung epithelial	Cr 0.5 mg/ml; mitosis dynamics, chromosome breakage	Not done	0.5 mg/ml		(0.5 mg/ml)^3	CA
(Babu et al., 1980)	Cells	CHO	Ch 10, 25, 50, 100, 200 μg/ml, chromosome aberrations	Not done (plateau)	10 μg/ml		(10 μg/ml)^3	CA
(Both et al., 1994)	Cells	Human lymphocytes	UICC: A Ch 50, 400 μg/ml; Cr 400 μg/ml(a) mutations, (b) LOH HLA-A locus	Not done (1 or 2 doses)	(a) Cr: no effect	(a) Ch 50 μg/ml(b) Cr 400 μg/ml	(400 μg/ml)^1	CA
(Both et al., 1995)	Cells	Human mesothelioma	UICC Cr: 50, 200 μg/ml(a) mutations, (b) LOH HLA-A locus	Not done (2 points)	(a) Effect not significant	(b) 50 μg/ml	[(b) 50 μg/ml]^1	CA
(Casey 1983)	Cells	CHO-K1	UICC Cr, Ch SFA: 0.001-0.01 μg/mlSCEs	Not done	No effect		(0.01 μg/ml)^2	CA
(Dopp et al., 1995b)	Cells	SHE	UICC: A Ch, Cr—micronucleus: Ch = 1, 5, 10 μg/cm^2; Cr = 1, 5, 10 μg/cm^2	Dose-effect ≈ plateau or decrease at the highest dose		1.0 μg/cm^2	(1.0 μg/cm^2)^1	CA
(Dopp et al., 1997)	Cells	Human amniotic fluid cells	UICC: A Ch, Cr, Amosite (Am): 0.5, 1, 5, 10 μg/cm^2 micronuclei w/wo kinetochore analysis, polyploidy, breakage	Micronuclei: dose effect, plateau breakage, hyperploidy: not done	Micronuclei: 0.5 μg/cm^2 breakage, hyperploidy: 1 μg/cm^2		(0.5 μg/cm^2)^1	CA
(Dopp et al., 1998)	Cells	SHE	UICC: A Ch, Crmicronucleus: 0.5, 1, 5, 10 μg/cm^2	Dose-effect plateau	All fibers = 0.5 μg/cm^2		(0.5 μg/cm^2)^1	CA
(Dopp et al., 1998)	Cells	Human amniotic fluid cells	UICC: A Ch, Crmicronucleus: 0.5, 1, 5, 10 μg/cm^2	Dose-effect plateau	All fibers = 1 μg/cm^2		(1 μg/cm^2)^1	CA
(Dopp et al., 2005)	Cells	V79	UICC Ch 1 μg/cm^2— micronucleus (± kinetochore Ab)	Not done (1 dose)		1 μg/cm^2	(1 μg/cm^2)^1	CA
(Durnev et al., 1993)	Cells	Blood lymphocytes, human	Ch Russia, 50 μg/ml—chromatid and chromosome breaks	Not done (1 dose)		50 μg/ml	(50 μg/ml)^1	CA
(Emerit et al., 1991)	Cells	Blood lymphocytes	Clastogenicity of chrysotile-treated rat pleural mesothelial cellls, 0.2–2 μg/m^2	Dose-effect		0.2 μg/cm^2 (no effect = toxcity at 2 μg/cm^2)	(0.2 μg/cm^2)^1	CA
(Hart et al., 1992)	Cells	CHO	UICC: A Ch, Cr(a) proliferation: Ch: 1, 2; Cr: 5 μg/cm^2— (b) colony forming efficiency (CFE): Cr: 5 μg/cm^2—(c) Nuclear abnormalities (NA): Ch: 1, 2, 5; Cr: 5 μg/cm^2	Not done (2 points)	UICC: A Ch, Cr(a) i proliferation: Ch: 1; Cr: 5 μg/cm^2 (b) i CFE: Cr: 5 μg/cm^2 (c) h NA: Ch: 1; Cr: 5 μg/cm^2		(1 μg/cm^2)^3	CA
(Hesterberg et al., 1985)	Cells	SHE	Cr 1 μg/cm^2	Not done (1 dose)	1 μg/cm^2		(1 μg/cm^2)^3	CA
(Huang et al., 1978)	Cells	CHL (Chinese hamster lung)	Cr: (a) survival: 10, 20, 40 μg/cm^2— (b) chromosomal aberrations: 5 μg/cm^2— (c) mutagenesis (6TG^R cells): 5 μg/cm^2 or 8 μg/cm^2 or 20 μg/cm^2	Dose-effect log (a) Not done (one dose (b)) Not done (one dose (c))	(a) 10 μg/cm^2 (at 50%)	(b) 5 μg/cm^2 (c) 8 μg/cm^2 (one among 3 experiments)	(5 μg/cm^2)^1	CA
(Kelsey et al., 1986)	Cells	CHO fibroblasts	Cr: (a) ploidy, (b) clastogenicity, (c) SCEs (d) mutation HGPRT, and TK— 0, 5, 10 20, 50 μg/ml	Not done (1 or 2 doses)	(a) 5 μg/ml(b) No effect(c) No effect(d) No effect		(5 μg/cm^2)^1 (50 μg/ml)^2	CA
(Korkina et al., 1992)	Cells	Human lymphocytes	Ch: 0.01, 0.05 mg/ml—abnormal metaphases	Not done (2 doses)		0.01 mg/ml	(0.01 mg/ml)^1	CA
(Lavappa et al., 1975)	Cells	SHE	UICC Ch A: 0.1, 1, 10, 100 μg/ml	Dose-effect ≈ log		0.1 μg/ml	(0.1 μg/ml)^1	CA
(Levresse, et al., 1998)	Cells	Rat pleural meso - normal - TagSV40	UICC: A Ch, Cr 10 μg/cm^2 cell cycle arrest,micronuclei, aneuploidy,	Not done (1 dose)	Positive effect		(10 μg/cm^2)^3	CA
(Oshimura et al., 1984)	Cells	SHE	Ch, Cr(a) Mutation: 1, 2 μg/cm^2 (b) Transformation: 1, 2 μg/cm^2 (c) Cytogenetic (aneuploidy, polyploidy, binucleated cells, micronuclei): 0.5–2 μg/cm^2	(a) No mutation(b) No transformation(c) Dose effect		(c) 0.5 μg/cm^2: aneuploidy, polyploidy, binucleated; 1 μg/cm^2: micronuclei	(0.5 μg/cm^2)^1	CA
(Palekar et al., 1987)	Cells	V79	UICC Ch, Cr: (2 ml in T25: 10, 40, 60, 100 μg/ml = 0.8, 3.2, 4.8, 8 μg/cm^2)— (a) aneuploidy— (b) clastogenicity	(a) Dose-effect exon(b) Dose-effect (not simple)		(a) 0.8 μg/cm^2 (both types) (b) 3.2 μg/cm^2 (Cr)—0.8 μg/cm^2 (Ch)	(0.8 μg/cm^2 3.2 μg/cm^2)^1	CA
(Pelin et al., 1995b)	Cells	Cells MeT-5A meso human	UICC samples, micronuclei induction (a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2 UICC samples, binucelated cells (a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2	Micronuclei induction(a) Dose effect(b) Dose effect	Binucleated cells(a) 0.5 μg/cm^2; ≈ 10^6 F/cm^2 (b) 0.5 μg/cm^2; ≈ 10^6 F/cm^2	Micronuclei induction(a) 0.5 μg/cm^2 (b) 0.5 μg/cm^2	(0.5 μg/cm^2)^1	CA
(Pelin et al., 1995b)	Cells	Cells normal meso human	UICC samples, micronuclei induction(a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2 UICC samples, binucelated cells(a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2	Micronuclei induction(a) Dose effect(b) Dose effect	Binucleated cells(a) 0.5 μg/cm^2; ≈ 10^6 F/cm^2 (b) 0.5 μg/cm^2; ≈ 10^6 F/cm^2	Micronuclei induction(a) 0.5 μg/cm^2 (b) 0.5 μg/cm^2	(0.5 μg/cm^2)^1	CA
(Pelin et al., 1995b)	Cells	Cells rat liver epithelial (RLE)	UICC samples, micronuclei induction(a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2 UICC samples, binucelated cells(a) Ch A 0.5–2 μg/cm^2 (b) Cr 0.5–2 μg/cm^2	Micronuclei induction(a) Dose effect(b) Dose effect	Binucleated cells(a) 0.5 μg/cm^2; ≈ 10^6 F/cm^2 (b) 0.5 μg/cm^2; ≈ 10^6 F/cm^2	Micronuclei induction(a) 0.5 μg/cm^2 (b) 0.5 μg/cm^2	(0.5 μg/cm^2)^1	CA
(Pelin et al., 1995a)	Cells	Human primary mesothelial cells from six patients (noncancerous)	UICC Am: 1, 2 μg/cm^2— chromosomal aberrations	Not done (2 doses)	1 or 2 μg/cm^2 in 2 patients		(1 μg/cm^2)^1	CA
(Pietruska and Kane, 2007)	Cells	Murine mesothelial cell lines D9, D7—malignant mesothelioma cell lines, MeT-5A	UICC Cr—10 μg/cm^2— DSBs (γ-H2AX foci formation)—micronuclei—senescence	not done		10 μg/cm^2; all tests	(10 μg/cm^2)^1	CA
(Poser et al., 2004)	Cells	Cells normal meso human	UICCA Ch, Cr 0.25–5 μg/cm^2(a) micronuclei formation	(a) dose-effect	(a) 0.25 μg/cm^2		(0.25 μg/cm^2)^3	CA
(Price-Jones et al., 1980)	Cells	V79-4 (Chinese hamster cells)	UICC Cr: ≈ 0.25, 1;25, 3.75 μg/cm^2 (1, 5 or 15 μg/ml, 20ml/75cm^2)— (a) aneuploidy; (b) ECS	No effect			(3.75 μg/cm^2)^4	CA
(Sincock and Seabright, 1975)	Cells	Chinese hamster cells	Ch SFA, UICC Cr: 10 μg/ml— chromosome aberrations	No effect (1 point)			(10 μg/ml) ^4	CA
(Sincock et al., 1982)	Cells	Primary human fibroblasts	Ch SFA, UICC Cr: 10 μg/ml (25-cm^2 flasks => likely 5 μg/cm^2)— chromosome aberrations		10 μg/ml (5 μg/cm^2 ?) only in hamster cells		(10 μg/ml) ^3	CA
(Valerio et al., 1983)	Cells	Human lymphocytes	Ch, CR:10 μg/ml— (a) aneuploidy: (b) chromatid and chromosome aberrations	Not done (1 dose)		(a) 10 μg/ml(b) 10 μg/ml	(10 μg/ml) ^1	CA
(Wang et al., 1987)	Cells	Cells rat pleural meso	UICC Ch A, Cr: 5 μg/ml = 1 μg/cm^2—Metaphase abnormalities	Not done (1 dose)	1 μg/cm^2		(1 μg/cm^2) ^3	CA
(Yegles et al., 1993)	Cells	Cells rat pleural meso	Aneuploidy (Aneu), Anaphase-Telophase Abnormalities (ATA). Ch UICCB:0.5-2 μg/cm^2; CR UICC: 1–6 μg/cm^2	Dose-effect		Aneu: Cr = 4 μg/cm^2—ATA: Cr = 7 μg.cm^2 (1.8 and 2 μg/cm^2 signif in 1/3 expt); Ch = 1.0 μg/cm^2	(4 μg/cm^2 7 μg/cm^2) ^1	CA
(Yegles et al., 1995)	Cells	Cells rat pleural meso	Anaphase-Telophase Abnormalities (ATA). UICC samples Ch: several doses	Ch ≈ linear	NOEL Stanton's fibers = 2.5 × 10^5/cm^2		(2.5 × 10^5/cm^2)^2	CA
(Durnev et al., 1993)	Cells ex vivo	C57BL/6 mice, peritoneal fluid cells	Ch Russia IP: 50 mg/kg (≈ 1 mg/mice), then perit fluid and bone-marrow cellsChromatid and chromosome breaks	Not done (1 dose)		1 mg/mice	(1 mg/mice)^1	CA
(Lavappa et al., 1975)	Cells ex vivo	bone marrow cells	UICC Ch A: 0.4, 4, 40, 400 mg/kgIP micronucleus	No effect	NOAEL = 400 mg/kg			CA in vivo
(Topinka et al., 2004)	Cells ex vivo	Alveolar macrophages and type II from Big Blue	Am I.tr.: (a) 1, 2 mg; (b) 4 × 2 mg— (a) DNA-SB (comet); (b) micronucleus	(a) Dose-effect— ≈ log		(a) 2 mg in both cell types(b) 2 mg in macrophages; n.s. in type II	(2 mg)^1 & 4	CA
Note. #, Lowest effective dose: 1, sLOAEL: Surrogate lowest-observed-adverse-effect level. 2, sNOAEL: Surrogate no-observed-adverse-effect level. 3, pLOAEL: Potential lowest-observed-adverse-effect level. 4, pNOAEL: Potential no-observed-adverse-effect level. *Type of assay. “Chromo” = Chromosomal aberrations, SCEs, micronuclei.

TABLE 1C. Dose-Effect Relationship of Asbestos-Induced Mutagenic/Carcinogenic Responses—Mutagenesis

Reference	Study type	Assay system	Assay endpoints	Dose-response shape	Limit dose with response (significant?)	Limit significant (or dose)	Lowest effective dose^#	Type of assay*
(Both et al., 1994)	Cells	Human lymphocytes	UICC: A Ch 50, 400 μg/ml; Cr 400 μg/ml (a) mutations HLA-A locus, (b) LOH HLA-A locus	Not done (1 or 2 doses)	(a) Cr: no effect	(a) Ch 50 μg/ml(b) Cr 400 μg/ml	Ch: (a) (50 μg/ml)^1 (b) (400 μg/ml)^2 Cr: 400 μg/ml)^2	Mutagenesis
(Both et al., 1995)	Cells	Human mesothelioma	UICC Cr: 50, 200 μg/ml (a) mutations, (b) LOH HLA-A locus	Not done (2 points)	(a) Effect not significant	(b) 50 μg/ml	[(b) 50 μg/ml]^1 [(a) 200 μg/ml]^2	Mutagenesis
(Hei et al., 1992)	Cells	AL cells	UICC Ch— (a) survival: 1–40 μg/ml; (b) mutagenicity at HGPRT locus 20 μg/ml: (c) mutagenicity S1 locus	Dose-effect exp. (a) Not done (expression per survival) (b and c)	(a) 1 μg/ml = ≈ 0.2 μg/cm^2 (i 10%) (c) mutants at 2.5 μg/ml = ≈ 0.5 μg/cm^2		(0.5 μg/cm^2)^3	Mutagenesis
(Hei et al., 1995)	Cells	AL cells	UICC Ch— (a) survival: 1–40 μg/ml; (b) mutagenicity S1 locus 20 μg/ml—40 μg/ml = ≈ 8 μg/cm^2	Dose-effect exp. (a) Not done (1 dose) (b)	(a) 1μg/ml = ≈ 0.2 μg/cm^2 (i 10%) (b) 20 μg/ml = ≈ 4 μg/cm^2		(4 μg/cm^2)^3	Mutagenesis
(Huang, 1979)	Cells	CHL CCL39 (Chinese hamster lung)	Ch, Cr, Am: 10 μg/cm^2 (a) Cell growth— (b) mutagenesis (6TG^R cells)	Not done (1 dose)		All types mutagenic 10 μg/cm^2	(10 μg/cm^2)^1	Mutagenesis
(Huang et al., 1978)	Cells	CHL (Chinese hamster lung)	Cr: (a) survival: 10, 20, 40 μg/cm^2— (b) chromosomal aberrations: 5 μg/cm^2— (c) mutagenesis (6TG^R cells): 5 μg/cm^2 or 8 μg/cm^2 or 20 μg/cm^2	Dose-effect log (a) Not done (one dose (b)) Not done (one dose (c))	(a) 10 μg/cm^2 (i 50%)	(b) 5 μg/cm^2 (c) 8 μg/cm^2 (one among 3 experiments)	(8 μg/cm^2)^1	Mutagenesis
(Kenne et al., 1986)	Cells	CHO	UICC Cr: 1.2, 7.6, 15.3, 23 23 μg/cm^2—mutagenicity (HGPRT)	Linear (3 lowest doses; highest doses toxic)	1.5 μg/cm^2		(1.5 μg/cm^2)^3	Mutagenesis
(Okayasu et al., 1999b)	Cells	AL cells	UICCA Ch, tremolite (Tr) (a) survival = Ch: 1–10 μg/cm^2, Tr: 5–40 μg/cm^2—(b) mutation HPRT = Ch: 1–10 μg/cm^2, Tr: 5–80 μg/cm^2— (c) mutation S1 ^− = Ch: 1–2.5 μg/cm^2, Tr: 5–20 μg/cm^2	(a) Dose effect(b) No mutation(c) Mutation; Ch ≈ strong, Tr: dose effect	(a) Ch: 1 μg/cm^2; Tr: 15 μg/cm^2 (c) Ch: 1 μg/cm2; Tr: 5 μg/cm^2		[(c) 1 μg/cm^2 5 μg/cm^2]^3 [(b) 10 μg/cm^2 80 μg/cm^2]^4	Mutagenesis
(Oshimura et al., 1984)	Cells	SHE	Ch, Cr(a) Mutation: 1, 2 μg/cm^2 (b) transformation: 1, 2 μg/cm^2 (c) cytogenetic (aneuploidy, polyploidy, binucleated cells, micronuclei): 0.5–2 μg/cm^2	(a) No mutation(b) No transformation(c) Dose-effect		(c) 0.5 μg/cm^2: aneuploidy, polyploidy, binucleated; 1 μg/cm^2: micronuclei	(2 μg/cm^2)^2	Mutagenesis
(Park et al., 1998)	Cells	V79 (Chinese hamster cells) for hgprt G12 (transgenic Chinese hamster cells) for gtp	Cr : (a) survival G12: 3, 4.5, 6 μg/cm^2— (b) mutagenicity hprt— (c) mutagenicity gpt 3, 4.5, 6 μg/cm^2	(a) Dose-effect expo(c) Dose-effect expo	(b) No effect	(a) 3 μg/cm^2 (b) no effect(c) 4.5 μg/cm^2	(6 μg/cm^2)^1 & 2 (4.5 μg/cm^2)^1	Mutagenesis
(Reiss et al., 1982)	Cells	Adult rat liver (ARL-18)	UICC B Ch 0.001, 0.1 μg/mlTGr mutants	Not done	No increased mutation/ controls		(0.1 μg/ml)^4	Mutagenesis
(Reiss et al., 1983)	Cells	ARL-6 and ARL-18	UICC Ch (0.75, 1 μg/ml), Cr (20, 30 μg/ml), Am (10, 20 μg/ml): mutation HGPRT (6-TG^R)	No effect			(1 μg/ml 30 μg/ml)^4	Mutagenesis
(Xu et al., 2002)	Cells	AL cells	UICC Cr(a) ROS production 2–9 μg/cm^2 (b) cytotoxicity(c) CD59 mutation 2, 4 μg/cm^2	(a) Peak(b) Not done(c) Not done	(a) 2 μg/cm^2—peak 6 μg/cm^2 (b) 2 μg/cm^2 (c) 2 μg/cm^2	2 μg/cm^2	(2 μg/cm2)^3	Mutagenesis
(Xu et al., 2007b)	Cells	gpt delta transgenic mous primary fibroblasts	UICC Ch(a) cytotoxicity; 0.5–6 μg/cm^2 (b) spi ^− mutations; 0.5-4 μg/cm^2	(a) Exponential(b) ≈ Linear	(a) 0.5 μg/cm^2	(b) 1.0 μg/cm^2	(1.0 μg/cm2)^3 (0.5 μg/cm^2)^4	Mutagenesis
(Xu et al., 2007a)	Cells	AL cells karyoplasts, cytoplasts, whole cells	UICC Cr(a) ROS formation by cytoplasts 2–6 μg/cm^2 (b) NO induction whole cells 2–12 μg/cm^2 (c) CD59 mutation (karyo + cyto plasts)	(a) Dose effect(b) Peak(c) Not done	(a) 2 μg/cm^2 (b) 2 μg/cm^2—peak 6 μg/cm^2 (c) 4 μg/cm^2		(4 μg/cm^2)^1	Mutagenesis
(Kociok et al., 1999)	Animal	Rats	Cr: 2 mg ip—mesothelioma, mutation analysis	Not done (1 dose)	2 mg [4 tumors with mutation (= deletions) in 27 tumors analyzed		(2 mg)^3	Mutagenesis in vivo
(Rihn et al., 2000)	Animal	Transgenic F344 lacI rats (Big Blue)	Cr: nose-only exposure 5.75 mg/m^3—mutation	Not done (1 dose)		5.75 mg/m^3	(5.75 mg/m^3)^1	Mutagenesis in vivo
(Topinka et al., 2004)	Animal	Transgenic F344 lacI rats (Big Blue)	Am I.Tr.: (a) 1, 2 mg; (b) 4 × 2 mg—mutagenesis	Not done (2 doses)		2 mg	(2 mg)^1	Mutagenesis in vivo
(Unfried et al., 2002)	Animal	Transgenic F344 lacI rats (Big Blue)	UICC Cr: analysis of the greater omentum: (a) mutations: 2, 5 mg; (b) 8-OH-dG: 1, 2 mg	Not done (2 doses)	(a) 5 mg(b) 1 mg		(5 mg)^3	Mutagenesis in vivo
Note. #, Lowest effective dose: 1, sLOAEL: Surrogate lowest-observed-adverse-effect level. 2, sNOAEL: Surrogate no-observed-adverse-effect level. 3, pLOAEL: Potential lowest-observed-adverse-effect level. 4, pNOAEL: Potential no-observed-adverse-effect level. *Type of assay. “Muta” = Mutagenesis.

TABLE 1D. Dose-Effect Relationship of Asbestos-Induced Mutagenic/Carcinogenic Responses—Tumorigenesis

Reference	Study type	Assay system	Assay endpoints	Dose-response shape	Limit dose with response (significant?)	Limit significant (or dose)	Lowest effective dose^#	Type of assay*
(Altomare et al., 2005a)	Animal	Mice 129Sv/JNf2 (+/−) Heterozygous and wild type	UICC Cr: ip total: 3.2 mg/mouse (repeated dose of 400 μg every 21 d for 8 rounds) mesos	Not done (1 dose)	Wild type: 3.2 mg = 59% Nf2 (+/−): 3.2 mg = 85%		(3.2 mg)^3	Tumor
(Altomare et al., 2009)	Animal	MiceArf (+/−)	UICC Cr: ip total: 3.2 mg/mouse (repeated dose of 400 μg every 21 d for 8 rounds) mesos	Not done (1 dose)	Wild type: 81%, latent period 56 wkArf (+/−): 96%, latent period 42		(3.2 mg)^3	Tumor
(Davis et al., 1988)	Animal	Rat wistar	Ch: long, short ip = 0.25, 2.5, 25—Peritoneal tumors	Dose-effect (plateau)	25 mg = 95% (long); 91.7% (short) 2.5 mg = 91.7% (long); 33.3% (short) 0.25 mg = 66.6% (long); 0% (short)		(0.25 mg function of size)^3	Tumor
(Davis et al., 1988)	Animal	Rat wistar	Ch long, short—Inh 10 mg/m^3—lung tumors + mesos	Not done (2 doses)	57.5% (long); 20% (short) 4.2% ctrl		(10 mg/m^3 function of size)^3	Tumor
(Davis et al., 1978)	Animal	Rat	Ch UICCA 2, 10 mg/m^3 Cr UICC 5, 10 mg/m^3 Am = 10 mg/m^3 tumor incidence	Dose-effect ChNot done Cr	10 mg/m^3: 37.5% (Ch), 2.5% (Cr), 4.7% (Am) 2 mg/m^3: 21.4% (Ch), 6.9% (Cr) Ctrl = 0%	Ch 2 mg/m^3	(2 mg/m^3)^1	Tumor
(Davis et al., 1986)	Animal	Rat wistar	Am long, short—Inh 12 mg/m^3—lung tumors + mesos	Not done (1 dose)	35% (long); 2.4% (short)—Ctrl = 3.3%		(12 mg/m^3)^3	Tumor
(Davis et al., 1986)	Animal	Rat wistar	Am long, short—ip 25, 10 mg—Peritoneal tumors	Not done (2 doses)	25 mg = 95.8% (long); 4% (short) 10 mg = 88% (long); 0% (short)		(10 mg function of size)^3	Tumor
(Davis et al., 1991)	Animal	RatAF/Han	Ch, Cr, Am eight doses: 0.01—15 mg	Dose response—log	Ch: 0.01 mg—total fibers: 9.0E+07— <0.25 μm: 3.4E+07— >5 μm, <0.25 μm: 6.2E+05		(10 μg)^3	Tumor
(Davis et al., 1991)	Animal	RatAF/Han	Ch, Cr, Am eight doses: 0.01—15 mg	Dose response—log	Cr: 0.05 mg—total fibers: 1.1E+08— <0.25 μm: 9.0E+07− > 5 μm, <0.25μm: 5.3E+05		(50 μg)^3 (10 μg)^4	Tumor
(Davis et al., 1991)	Animal	RatAF/Han	Ch, Cr, Am eight doses: 0.01—15 mg	Dose response—log	Am: 0.01 mg—total fibers: 8.3E+06— <0.25 μm: 5.3E+06— >5 μm, <0.25 μm: 2.9E+04		(10 μg)^3	Tumor
(Fleury-Feith et al., 2003)	Animal	Mice FVB/NNf2 ^KO3/+ heterozygous and wild type	Cr,length: 9.9 ± 7.8 μm and diameter: 0.3 ± 0 .2 μm,: total 5 mg in separated two doses (2nd injection was 2 mo apart from the 1st injection). Peritoneal tumors	Not done (1 dose)	Wild type: 5 mg = 17% Nf2 (+/−): 5 mg = 47%		(5 mg)^3	Tumor
(Jaurand et al., 1987)	Animal	Rat Sprague-Dawley	UICC Am—20 mg—Pleural tumors	Not done (1 dose)	20/35		(20 mg)^1	Tumor
(Lippmann, 1994)	Animal	Rodents—Tumorigenicity—data from inhalation studies by Davis et al. and Pott et al.	Several samples	Dose response—polynomial: y = a+ bf + cf^2 with “c” << a and b	Correlation tumor incidence for fibers >5 μm length, >10 μm length		[≈ 1000 F/ml (L > 5 μm)]^3	Tumor
(Marsella et al., 1997)	Animal	Mice 129Svp53 ^−/− p53 ^+/− and p53 ^+/+	UICC Cr: weekly ip of 200 μg for 35 wk mesos	Not done (1 dose)	Wild type: 32%, latent period 67 wkP53 (+/−): 76%, latent period 44 wkP53 (−/−): 12.5%, latent period 10 wk		(7 mg)^3	Tumor
(Monchaux et al., 1981)	Animal	Rat Sprague-Dawley	UICC Cr—I Pleural 20 mg—Pleural tumors	Not done (1 dose)	21/32		(20 mg)^3	Tumor
(Monchaux et al., 1981)	Animal	Rat Sprague-Dawley	ChA—I Pleural20 mg—Pleural tumors	Not done (1 dose)	15/32		(20 mg)^3	Tumor
(Vaslet et al., 2002)	Animal	Mice 129/Sv strain on a 75% C57B1/6 background, p53 ^+/− and p53 ^+/+	UICC Cr: weekly ip of 200 μg for 35–66 wk until tumor develops	Not done (1 dose)	Wild type:32%, latent period 67 wkP53 (+/−): 76%, latent period 44 wk		(7–13.2 mg)^3	Tumor
(Wagner et al., 1973)	Animal	Rat wistar	ChB—I Pleural 20 mg—Pleural tumors	Not done (1 dose)	10/32		(20 mg)^1	Tumor
(Wagner et al., 1973)	Animal	Rat wistar	ChA—I Pleural 20 mg—Pleural tumors	Not done (1 dose)	7/31		(20 mg)^1	Tumor
(Wagner et al., 1973)	Animal	Rat wistar	UICC Cr—I Pleural 20 mg—Pleural tumors	Not done (1 dose)	18/32		(20 mg)^1	Tumor
(Wagner et al., 1974)	Animal	Rat wistar	UICC Ch A, Ch B—Inh 10 mg/m^3—lung tumors + mesos	Not done (1 dose)	11/21 (ChB), 11/17 (ChA)		(10 mg/m^3)^1	Tumor
(Wagner et al., 1974)	Animal	Rat wistar	UICC Am—Inh 10 mg/m^3—lung tumors + mésos	Not done (1 dose)	13/21		(10 mg/m^3)^1	Tumor
(Wagner et al., 1974)	Animal	Rat wistar	UICC Cr—Inh 10 mg/m^3—lung tumors + mesos	Not done (1 dose)	13/18		(10 mg/m^3)^1	Tumor
(Hei et al., 1984)	Cells	C3H10T1/2	UICC Ch, Am	No effect (1 point)	5 μg/ml			Transformation
(Hesterberg and Barrett, 1984)	Cells	SHE	UICC Ch, Cr: 0.25–2 μg/cm^2 (a) survival— (b) transformation frequency	dose-effect expon. (a) dose-effect linear; slope ≈ 1; one hit compatible (b)	EC-50 (a) = 0.9 (Ch), 1.7 (Cr) μg/cm^2— (b): 0.25 μg/cm^2;		(0.25 μg/cm^2)^3	Transformation
(Lu et al., 1988)	Cells	BALB/3T3	UICC Ch, Cr—Transformation assayCh = 0.005-0.5 μg/cm^2 Cr = 0.1–10 μg/cm^2	Ch: dose effectCr: no dose effect	Ch: 0.005 μg/cm^2 Cr ≈ 0.1 μg/cm^2		(0.005 μg/cm^2 0.1 μg/cm^2)^3	Transformation
(Mikalsen et al., 1988)	Cells	SHE	Ch, Cr, Am, Anthophyllite: 0.5, 1.5, 3, 5 μg/cm^2—Transformation assay	Dose-effect ≈ plateau (depends on exptl conditions)	1% transformation in μg/cm^2: 0.15 (Ch), 2.6 (Cr), 3.0 (Am), 3.5 (Anth)	Cr = 1.5 μg/cm^2	[1.5 μg/cm^2]^3 [0.5 μg/cm^2]^4	Transformation
(Oshimura et al., 1984)	Cells	SHE	Ch, Cr(a) Mutation: 1, 2 μg/cm^2 (b) transformation: 1, 2 μg/cm^2 (c) cytogenetic (aneuploidy, polyploidy, binucleated cells, micronuclei): 0.5–2 μg/cm^2	(a) No mutation(b) Dose effect(c) Dose effect		(c) 0.5 μg/cm^2: aneuploidy, polyploidy, binucleated; 1 μg/cm^2: micronuclei	(2 μg/cm^2)^2	Transformation
Note. #, Lowest effective dose: 1, sLOAEL: Surrogate lowest-observed-adverse-effect level. 2, sNOAEL: Surrogate no-observed-adverse-effect level. 3, pLOAEL: Potential lowest-observed-adverse-effect level. 4, pNOAEL: Potential no-observed-adverse-effect level. *Type of assay. “Tumor” = Tumor, “Transfo”= Transformation.

TABLE 1E. Dose-Effect Relationship of Asbestos-Induced Mutagenic/Carcinogenic Responses—Cellular Responses

Reference	Study type	Assay system	Assay endpoints	Dose-response shape	Limit dose with response (significant?)	Limit significant (or dose)	Lowest effective dose^#	Type of assay*
(Belitskaya-Levy et al., 2007)	Cells	Normal human bronchial epithelial	UICC Ch: 7, 12.7 μg:cm^2— gene expression	Not done (1 dose)	7 μg/cm^2		(7 μg/cm^2)^3	Cell responseGene expression
(Broaddus et al., 1996)	Cells	Cells meso rabbit	Cr, Am, Ch(a) decreased proliferation(b) enhanced apoptosis	Dose-effect		(a) Cr: 3 μg/cm^2— (b) Cr: 3 μg/cm^2, Am:15 μg/cm^2, Ch: 10 μg/cm^2		Cell responseApoptosis
(Cole et al., 1991)	Cells	Taricha granulosa—primary epith & mesoth lung cells	UICC Cr: 500 μg/ml	Not done (1 dose)	migration of <5 μm L fibers, not long fibers			Cell responseInteraction with microtubules
(Dubes and Mack, 1988)	Cells	CLI (chimpanzee liver), KB human K, Eta monkey kidney, NIH 3T3	13 asbestos samples—1.42—142 μg/cm^2	Not done	not provided			Cell responseTransfection of viral RNA
(Hart et al., 1994)	Cells	CHO	NIEHS Cr long, Cr med, Cr short—UICC Ch, Cr and MMVF [all types gathered according to size parameters]— ≈ 1–200 μg/cm^2 or ≈12,000–150,000 fibers/cm^2 (a) Cytotoxicity (decreased proliferation) (b) Abnormal nucleus induction (ANI)	Dose-effect (a) and (b) dependence with length; slight dependence with diameter		(a) 0.68 to 3.0 μg/cm^2 or 0.8 to 45 × 10^5 fibers/cm^2		Cell response (viability)
(Jiang et al., 2008)	Cells	RAW264.7, HeLa, Met-5A, FRCC562 (rat renal carcinoma ferric nitrilotriacetated-induced)	UICC A ch, Cr, Am = 5 μg/cm^2 (a) phagocytosis— (b) ROS level in RAW264.7: 1–10 μg/cm^2	Not done	(a) Uptake: all fiber types in all cell types; fibers in the nucleus(b) Ch = n.s.	(b) Cr = 3 μg/cm^2; Am = 5 μg/cm^2		Cell response (genotoxic potential)
(Johnson et al., 1997)	Cells	A549 human epithelial	UICC Cr: 0.1, 0.5, 1, 2, 5 μg/cm^2—Cell cycle effects (a) h % G2 cells; h p21, h p53, h Gad43.	Dose response—log	0.5 μg/cm^2		(0.5 μg/cm^2)^3	Cell response (genotoxic potential)
(Levresse et al., 1997)	Cells	Rat pleural meso	UICC A Ch: 0, 5, 10 μg/cm^2; Cr: 0, 10, 20 μg/cm^2	Dose-effect— ≈ linear		Ch: 5 μg/cm^2 Cr: 10 μg/cm^2	(5 μg/cm^2)^3	Cell response (genotoxic potential)
(Lu et al., 1994)	Cells	V79 (Chinese hamster lung)	NIEHS Ch: intermediate, short treated with surfactant— (a) micronucleus— (b) SCEs	Not applicable				Cell responseChromo—fibers treated with surfactant
(Matsuoka et al., 2003)	Cells	A549 human epithelial	UICC ACh, Cr: 1–10 μg/cm^2 p53 phosphorylation	Dose-effect	1 μg/cm^2 (Western)			Cell responseDNA—indirect
(Yang et al., 2006)	Cells	Cells normal meso human	(a) Cytotoxicity 0.2–5 μg/cm^2 (b) TNF-alpha and receptor production 6–24 μg/cm^2	(a) Dose effect(b) Dose effect (no stats) (c) Not done	(b) 6 μg/cm^2	(a) 0.5 μg/cm^2		Cell responseChromo (no dose provided)
(Rita and Reddy, 1986)	Cells ex vivo	Mice germinal cells	Ch—oral feeding					Cell responseChromo in germinal cells—oral feeding
Note. #, Lowest effective dose: 1, sLOAEL: Surrogate lowest-observed-adverse-effect level. 2, sNOAEL: Surrogate no-observed-adverse-effect level. 3, pLOAEL: Potential lowest-observed-adverse-effect level. 4, pNOAEL: Potential no-observed-adverse-effect level. *Type of assay. “Cell response” = cellular changes in response to asbestos treatment: i.e., phagocytosis, increased intracellular ROS level, changes in the expression/function of signaling molecules involved in cell cycle, apoptosis, DNA repair, or other pathways.

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