The World Health Organization (2010) indoor air guideline value on formaldehyde

and recent scientific studies

Gunnar Damgård Nielsen PhD, Dr Sc (Pharm)

National Research Centre for the Working Environment, Denmark

Updated: 30.01.2015

WHO guidelines for indoor air quality. Selected pollutants.

WHO, Regional Office for Europe, Copenhagen, 2010.

A short-term (30 min) guideline of 0.1 mg/m3 was recommended for preventing sensory irritation in the general population; it applies to all periods during a day.

Also, the value was considered to prevent cancer.

Physicochemical properties of FA

Properties Values

Reaction with –OH, -NH2 or = NH, -SH a)

Melting point -92ºC a,b)

Boiling point -19ºC a,b)

Water solubility 400g/L at 20ºC a,b)

Vapour pressure 3886 mmHg at 25ºC a,b)

a) WHO 2010

b) http://chem.sis.nlm.nih.gov/chemidplus/

N. vagus (X)

N. trigeminus (V) N. Glosso-

pharyngeus (IX)

Shusterman D. Review of the upper airway, including olfaction, as mediator of

symptoms. Environ Health Perspect 2002; 110 (suppl.4): 649-653.

Portal-of-entry effects

Eyes and nose for FA

Formaldehyde toxicokinetics (WHO 2010)

Absorbed mainly in the upper airways (>90%)

Reacts with glutathione (HO-CH2-SG), proteins,

RNA and DNA

GSH-adduct is oxidized to formate (Km(rats)~ 2.6

ppm)

Exposure above the Km value, FA increases

disproportionate in nasal tissue

Inhalation causes no increase in blood FA

T1/2~1.5 min in plasma

Formed endogenously (blood: 2-3 mg FA/L; FA in

exhaled air: mean~ 2 ppb and 75th percentile~6

ppb)

New studies on nasal and lung uptake of formaldehyde

At ≥0.1 ppm estimated nasal FA uptake in rats,

monkeys and humans is ~99, 87 and 85%,

respectively, using anatomically accurate

computational fluid dynamics models a)

Toxicodynamic calculations: Bypassing the nose and

mouth, FA is mainly deposited in the trachea and no

FA reaches the deep lung parts and no FA was

predicted to be absorbed into the blood in humans b)

a) Schroeter et al. Effects of endogenous formaldehyde in nasal tissues on

inhaled formaldehyde dosimetry predictions in the rat, monkey, and human

nasal passage. Toxicol Sci 2014, in press.

b) Asgharian et al. A lung dosimetry model of vapour uptake and tissue

disposition. Inhal Toxicol 2012; 24: 182-193

Nasal formaldehyde (FA) metabolism

Inhaled FA (CH2O)

Mucus layer FA (CH2(OH)2)

(formaldehyde acetal)

Epithelial cell membrane

CH2(OH)2 Reacts with

DNA and

proteins GSH

●DNA adducts3)

●N6-formyllysine4)

●Gene expression1,2)

● Adducts with mucus

layer and cell surface

constituents from

gene expression1,2)

HO-CH2-SG

FDH

HCOO- + GSH

1. Andersen et al. Toxicol Sci 2010, 118, 716-731.

2. Andersen et al. Toxicol Sci 2008, 105, 368-383.

3. Swenberg et al. Toxicol Sci 2011,120(S1): S130-S145.

4. Edrissi et al. Chem Res Toxicol 2013; 26: 1421-1423.

Biomarkers:

No adducts outside

the nasal cavity

from inhalation

New ADME relevant studies since WHO (2010)

1. Rats exposed to 0, 0.7, 2, 6, 10 and 15 ppm 6h/day for

1, 4 or 13 weeks a):

Effects at 0.7 to 2 ppm in nasal epithelial cells:

• CH2(OH)2, DNA-protein cross-links, GSH-FA increased

slightly and GSH decreases slightly

• Several ppm FA is required for significant changes

• Genomic changes reflects extracellular changes in

CH2(OH)2 and GSH

• FA below 1-2 ppm had no effect on intracellular

homeostasis

a) Andersen et al. Toxicol Sci 2010; 118: 716-731.

New ADME relevant studies since WHO (2010)

2. Only exogenous DNA adducts in the nose in rats and

monkeys

Nonlinear DNA adduct formation from exogenous FA b)

3. Only exogenous N6-formyllysine in the nose in rats at

≤ 9 ppm c)

4. Rats exposed to 10 ppm 13C-FA for 6 h: No increase in

blood 13C-FAd)

b) Swenberg et al. Toxicol Pathol 2013; 41: 181-189.

c) Edrissi et al. Chem Res Toxicol 2013; 26: 1421-1423.

d) Kleinnijenhuis et al. Food Chem Toxicol 2013; 52: 105-112.

Portal-of-entry effects

I. Sensory irritation of eyes and upper

airways

II. Asthma: not supported by the WHO

(2010) or recent studies

III. Nasal genotoxicity and cancer

I. Sensory irritation of eyes and upper airways

Paustenbach et al. (1997) reviewed all data

in animals and humans:

No eye irritation at 0.5 ppm

Proposed no irritation at < 0.1 ppm (24 h/day) in

the general population.

No especially sensitive group (including

asthmatics) was identified.

Epidemiological studies: Mixed exposures (less

valuable)

Paustenbach D, Alarie Y, Kulle T, Schachter N, Smith R, Swenberg J,

Witschi H, Horowitz SB. A recommended occupational exposure limit

for formaldehyde based on irritation. J Toxicol Environ Health 1997, 50: 217-263.

Key study by WHO (2010): Lang et al. (2008)a

Controlled chamber study: 11M and 10 F, age:18-40 y,

exposured for 4 h

Eye and airway effects: NOAEL 0.5 ppm FA;

LOAEL 0.5 ppm with peaks at 1 ppm

AF: 5 and rounding to 0.1 mg/m3. The WHO guideline

applies to each 30 min period of the day

a) Lang I, Bruckner T, Triebig G. Formaldehyde and chemosensory irritation in humans:

a controlled human exposure study. Regul Toxicol Pharmacol 2008, 50: 23-36.

b) Mueller JU, Bruckner T, Triebig G. Exposure study to examine chemosensory effects

of formaldehyde on hyporsensitive and hypersensitive males.

J Arch Occup Environ Health 2013, 86: 107-117.

New chamber study :

NOAEL 0.7 ppm; LOAEL 0.4 ppm with peaks at 0.8 ppm

(hypo- and hypersensitive males) b)

Sensory irritation: day after day exposure?

A 10-day study (1 h/day) in mice with a limonene-ozone

mixture b)

It contained volatile organic compounds and FA a)

FA accounted for ¾ of the sensory irritation effect a)

Low to very high sensory irritation effects were studied b)

No increase in sensory irritation or airflow limitation over

repeated exposures and no inflammation was observed b)

Chamber studies adequately reflect long term effects.

a) Wolkoff et al. Acute airway effects of ozone-initiated d-limonene chemistry:

importance of gaseous products. Toxicol Lett 2008, 181: 171-176.

b) Wolkoff et al. Airway effects of repeated exposures to ozone-initiated limonene

oxidation products as model of indoor air mixtures. Toxicol Lett 2012, 209: 166-172

Effect of formaldehyde on the respiratory rate in mice

Nielsen et al. Hum Exp Toxicol 1999; 18: 400-409

Secondary effects of sensory irritation

Effect of formaldehyde on the expiratory flow rate in mice

Nielsen et al. Hum Exp Toxicol 1999; 18: 400-409

Hypoxia

Repetitive obstruction of the upper airways in animals

and humans (e.g. obstructive sleep apnoea) causes

Biochemical effects:

1. Activation of NADPH oxidase

2. Xanthine oxidase

3. Mitochondrial chain electron leakage

4. Induction of NO synthase

Pathology:

1. Oxidative stress

2. Inflammation

3. Activation of the sympathetic NS

Clinical effects:

1. Adverse cardiovascular effects

2. CNS impairments

II. Asthma

FA does not cause asthma in itself a) (except RADS)

No lung function effects of FA (< 1 mg/m3) in asthmatics and non-

asthmatics b)

Pre-exposure to FA in asthmatics and post exposure to an allergen to

which subjects were sensitized showed no consistent increase in

allergen sensitivity b)

No convincing association between FA exposures in homes and

schools and asthma in children and adults b,c,d).

New epidemiological studies:

- One found a positive association in the group with the

lowest (rural) FA exposure (Hulin et al. 2010):.

- Two found no association (Hwang et al. 2011; Kim et al. 2011).

Meta-analysis (McGwin et al., 2010): Significant association between

FA exposure and asthma in children. Most influential studies were the

Rumchev et al. (2002) and the Garret et al. (1999) studies.

a) Paustenbach et al. J Toxicol Environ Health 1997, 50: 217-263. b) Wolkoff and

Nielsen. Environ Int 2010, 36: 788-799. c) Heinrich J. Int J Hyg Environ Health 2011;

214: 1-25. d) Nielsen et al. Arch Toxicol 2013; 87: 73-98.

III. Portal-of-entry

genotoxicity and carcinogenicity

Animal studies:

• Nasal genotoxicity is well established

non-linear exposure-response relationships)

• Nasal cancer: Key effect in cancer risk assessment by

the WHO (2010)

Human studies:

• Portal-of-entry genotoxicity is not that clear

• Nasopharyngeal cancer was mainly based on results

from the NCI cohort (Hauptmann et al. 2004).

Hauptmann et al. Am J Epidemiol 2004, 159: 1117-1130.

Beane Freeman et al. Am J Ind Med 2013; 56: 1015-1026.

• New update (Beane Freeman et al. 2013)

Buccal and/or nasal genotoxicity in humans

Increased micronucleus formation (MN): • Limited consistency within and across epidemiological studies a)

• Studies have potential confounders a)

• Controlled exposure study at 4 h/day for 10 working days at

0.15-0.5 ppm FA with peaks at 0.6 and 1 ppm. Buccal cells:

No significant increase b) Relevance?

• Where present (WHO, 2010), associated with high mean and/or

high peak exposures c)

• High peak exposures in recent epidemiological studies d,e)

• Controlled exposure study 4h/day for 5 days. FA ≤ 0.7 ppm, peaks

op to 0.8 ppm. Nasal epithelial cells: No increase in MN in nasal

biopsies: No remarkable change in gene expression f)

a) Speit and Schmid. Mutat Res 2006, 613: 1-9; b) Speit et al. Mutat Res 2007, 627: 129-135; c)

Nielsen and Wolkoff. Arch Toxicol 2010, 84: 423-446;d) Viegas et al. J Occup Med Toxicol 2010, 5:

25; e) Ladeira et al. Mutat Res 2011, 721: 15-20; f) Zeller et al. Mutagenesis 2011, 26: 555-561.

Recent studies:

Nasal epithelial cell FA-DNA adducts a) and squamous cell carcinomas (SCCs) in rats exposed 6 h/day, 5 days/week to

formaldehyde for ≥ 2 years b)

Formaldehyde (ppm)

Exogenous N2-HOC H2-dG/ Endogenous N2-HOC H2-dG

Number with SCC/group size (%)

0 - 0/453 (0)

0.3 - 0/32 (0)

0.7 0.011 0/90 (0)

2 0.033 0/364 (0) Apparent NOAEL

6 0.19 3/325 (0.9) Apparent LOAEL

10 0.60 20/90 (22)

14 - 103/232 (44)

15 2.79 120/278 (43)

a) Lu et al. Chem Res Toxicol 2011; 24: 159-161; a single 6 h exposure in rats.

b) Studies: Kerns et al. (1983), Sellakumar et al. (1985), Monticello et al. (1996), Kamata et

al.(1997); for full references c.f. Nielsen and Wolkoff. Arch Toxicol 2010, 84: 423-446.

Nasopharyngeal cancer death in 25,619 workers Recent update of the US NCI cohort a)

Peak exposure level Average exposure intensity Cumulative exposure

ppm and

P trend

RR (95%CI) and

(cases)

ppm RR (95%CI)

(cases)

ppm x y RR (95%CI) (cases)

Non-exposed 4.4 (0.3-54) (2) “0” 6.8 (0.5-84) (2) 0 1.9 (0.3-12) (2)

>0 - < 2.0 RR=1 (1)

Reference

0.1 - 0.4 RR=1 (1)

Reference

>0- <1.5 RR=1 (4)

Reference

2.0 - < 4.0 Not applicable (0)

Apparent NOAEL

0.5 -0.9 2.4 (0.15-39) (1)

Apparent NOAEL

1.5-<5.5 0.86 (0.1-7.7) (1)

≥ 4.0 7.7 (0.9-62) (7) ≥ 1.0 12 (1.4-97) (6) ≥ 5.5 2.9 (0.6-13) (3)

(?)

P (0+FA )

P (FA)

P=0.10

P<0.005

P=0.16

P=0.09

P=0.07

P=0.06

Beane Freeman et al. Mortality from solid tumors among workers in formaldehyde industries:

an update of the NCI cohort. Am J Ind Med 2013; 56: 1015-1026

Non-linear exposure-response relationships, 5 cancers in one plant

WHO 2010 and nasopharyngeal cancer (NPC)

Based on the Hauptmann et al. (2004) study and now

supported by the recent update (Beane Freeman et al. 2013):

No excess NPC at mean concentrations ≤ 1 ppm FA and at

peak concentrations below 4 ppm

Effect supported from the rat studies

For the guideline setting, the NOAEL at 1 ppm for

histopathological effects in rats was used as point of departure

and considered to prevent NPC in humans. Accommodates cell

proliferation in rats (LOAEL ~ 2 ppm) and SCC (NOAEL ~2

ppm)

Study NCI cohort a,b)

(N=25,619)

UK cohort c)

(N=14,014)

US garment workers d)

(N=11,039)

Exposure (ppm) Median average

intensity: 0.3 and

range: 0.01-4.3

15% ≥ 1 ppm

24% had peaks ≥4

Range: 0.1 to >2 Geometric mean: 0.15.

GSD: 1.9.

Past exposure: Substantial higher

All cancers 1.08 (RR<1 at top exp) 1.10 0.96

Nose and sinuses 0.90 0.71 0.00 (O/E: 0/0.95)

Pharynx - 1.20 0.88

Nasopharynx 1.84 (95%CI: 0.8-3.5) 0.59 (O/E: 1/1.7) 0.00 (O/E: 0/1.33)

Larynx 1.23 1.22 0.77

Lung 1.14e) 1.26 (smoking?) 1.04

Hodgkin’s disease 1.42 - 0.95

Non-Hodgkin’s lymphoma 0.85 1.06 1.13

Multiple myeloma 0.94 0.99 1.24

Leukemia 1.02 1.02 1.04

Lymphatic leukemia 1.15 - 0.71

Myeloid leukemia 0.90 1.20 1.28 ( 10+ y exp and 20+ y since first exp)

Standardized mortality ratios. The three occupational cohorts used in WHO

(2010) have been updated recently

a) Standardized mortality ratio. Where 95% CI does not include 1, it is indicated by bold and red. b) NCI updated through 2004

(Beane Freeman et al. 2009; 2013). c) Coggon et al. (2014). d) Meyers et al. (2013)

e) RR at highest category: peak (0.77), average intensity (1.0) and cumulative exposure (0.78)

Lymphohematopoietic malignancies

Animal studies: Not convincing, but if present only ~15 ppm and with a

non-linear exposure-response relationship

Human studies: The WHO (2010) analyzed the studies for:

● Exposure-response relationships?

● If non-linear, apparent NOAEL?

● Establishing levels, which the guideline level

has to be below to be contradiction free

Relative risk (RR) of lymphohematopoietic malignancies in humans a)

Disease Lympho-

hemato-

poietic

malign-

ancies

ICD-8:

200-209

Non-

Hodg-

kin’s

lympho

-ma

ICD-8:

200 &

202

Hodg-

kin’s

lympho

-ma

ICD-8:

201

Myeloid

leuke-

mia

ICD-8:

205

Multip-

le

myelo-

ma

ICD-8:

203

Disease Lympho-

hemato-

poietic

malignanci

es

ICD-8: 200-

209

Non-Hodg-

kin’s

lympho-ma

ICD-8: 200

& 202

Hodg-

kin’s

lympho-

ma

ICD-8:

201

Myeloid

leuke-

mia

ICD-8:

205

Multiple

myelo-

ma

ICD-8:

203

ppm Average intensity ppm Peak exposure

0

0.99 1.08 0.53

.11-2.6

0.70

.23-2.16

2.18*

1.01-4.7

0 1.07 1.06 0.67 0.82 2.74*

1.18-6.37

>0-<0.5

Ref. gr.

1.00 1.00 1.00

NOAEL

(?)

1.00 1.00 >0-<2.0

Ref.gr.

1.00 1.00 1.00

NOEL

(?)

1.00 1.00

0.5-<1.0 1.29 1.20 3.62*

1.41-9.3

1.21

.56-2.62

1.40 2.0-<4.0 1.17

NOAEL (?)

1.08 3.30*

1.04-11

1.30 1.65

0.76-3.61

NOAEL

(?)

≥ 1.0 1.07 0.71 2.48

.84-7.3

1.61

.76-3.39

1.49 ≥4.0 1.37*

1.03-1.8

0.91 3.96*

1.31-12

1.78

0.87-3.6

2.04*

1.01-4.12

P(0+FA)

P(FA)

>0.50

>0.50

0.40

>0.5

0.03*

0.05*

0.40

0.43

>0.50

>0.50

P(0+FA)

P(FA)

0.04

0.02

>0.50

>0.50

0.004

0.01

0.07

0.13

>0.50

0.08

Beane Freeman et al. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: the National

Cancer Institute Cohort. J Natl Cancer Inst 2009, 101, 751-761.

a) Sometimes added 95% confidence limits. Figures marked with * and red are significant.

Cumulative exposures (ppm-y) showed no association at all

Occupational related to lymphohematopoietic malignancies

Disease Exposure

Non-Hodgkin’s lymphoma

Benzene, trichloroethylene, agriculture/farmers, abattoir (butcher) workers (viruses?), herbicides and pesticides

Hodgkin’s lymphoma Agriculture/farmers, abattoir workers (viruses?), EBV

Leukemia Benzene (AMLa)), gasoline (3-5% benzene), ionizing radiation (AML), dioxins (TCDD)?, butchers (viruses?), agriculture/farmers (CLL), 1,3-butadiene, embalmers and formaldehyde exposed workers, treatment with alkylating agents, rubber industry (CLL, benzene?), arsenic, cigarette smoking (9% of AML?), pesticides

Multiple myeloma Engine exhaust, teachers, pesticides,

a) Acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL).

1) Descatha et al. Occupational exposures and haematological malignancies: overview on human recent data.

Cancer Causes Control 2005, 16, 939-953.

2) Blair et al. Chemical exposures and risk of chronic lymphocytic leukaemia. Br J Haematol 2007, 139, 753-761.

3) Natelson Benzene-induced acute myeloid leukemia: a clinician’s perspective. Am J Hematol 2007, 82, 826-830.

4) Steinmaus et al. Meta-analysis of benzene exposures and non-Hodgkin lymphoma: biases could mask an important association.

Occup Environ Med 2008, 65, 371-378.

5) Van Maele-Fabry et al. Risk of leukaemia among pesticide manufacturing workers: a review and meta-analysis of cohort studies.

Environ Res 2008, 106, 121-137.

6) Merhi et al. Occupational exposure to pesticides and risk of hematopoietic cancers: meta-analysis of case-control studies.

Cancer Causes Control 2007, 18, 1209-1226.

7) Lichtman MA. Cigarette smoking, cytogenetic abnormalities, and acute myelogenous leukemia. Leukemia 2007, 21, 1137-1140.

The WHO (2010) indoor air guideline value Critical effect: sensory irritation

NOAEL: 0.5 ppm (now 0.7 ppm), using an AF: 5 and rounding:

Guideline value: 0.1 mg/m3 (0.08 ppm) (30-min average concentration)

Nasal cancer risk assessment (WHO 2010)

Point of departure: 1 ppm NOAEL for histopathological effects and nasal

cell proliferation in rats; AF: 3 for interspecies variation (local effect) and

AF: 2 for variation in the human population: 0.17 ppm (0.2 mg/m3) for

prevention of nasal cancer

Biologically motivated model: 0.25 mg/m3 predicts an additional risk ≤ 10-6

for continuous exposure of non-smokers a)

Supporting evaluations of cancer effects

The 1 ppm point of departure: no interspecies AF (rat is the sensitive

species). Being precautionary, AF: 10 for intra human variations, suggesting

that 0.1 ppm (0.12 mg/m3) would prevent nasal cancer b)

The guideline accommodates NOAEL for lymphohematopoietic cancers

a) Conolly et al. Toxicol Sci 2004, 82: 279-296.

b) Nielsen and Wolkoff. Arch Toxicol 2010, 84: 423-446.

The guideline has no contradiction with observed results