WOOD DUST & WESTERN RED CEDAR- (6/9/10)---L. Morse MD (with thanks to Bob Barish, Scott McAllister and Paul)

SUMMARY: Wood dust exposure has been documented in dozens of reports from around the world as the cause of allergic lung disease , non allergic pulmonary disease, and sinonasal cancer. Less frequently, wood dust has been described as causing alveolitis, pulmonary fibrosis, dermatitis and other cancers. A summary document by ACGIH in 2005 proposed a TLV of 1 mg/M3 for wood dust in general, and 0.5 mg/M3 for Western Red Cedar, with a sensitizer designation. The conclusion ACGIH reached was based on it’s extensive review of the literature. (ACGIH released it’s “final” document in 2010 with the same conclusion but without updating the literature review.) ACGIH in the TLV designated oak and beech dusts with respect to carcinogenicity as 1A - Confirmed Carcinogens, and birch, mahogany, teak, and walnut as A2 Suspected Human Carcinogens. The ACGIH TLV designates all other wood dusts as A4 - Not Classifiable as Human Carcinogens. The U.S. National Toxicology Program (NTP) in its 11th Report on Carcinogens (11th ROC, 2005) designates wood dust as being “Known to be a human carcinogen” based on sufficient evidence of carcinogenicity from studies in humans, while also noting there is inadequate evidence for the carcinogenicity of wood dust from studies in experimental animals. The International Agency for Research on Cancer (IARC) in its document last updated in 1997 similarly has classified wood dust as being Group 1 Carcinogenic to humans, stating there is sufficient evidence in humans for the carcinogenicity of wood dust, and inadequate evidence in experimental animals for the carcinogenicity of wood dust. Most recently, California’s OEEHA added wood dust to the Prop 65 list of carcinogens.

An extensive review of the literature was performed for the development of this report for HEAC. Overall, there seems to have been a decline in exposure levels compared to older studies, with corresponding decrease in positive associations. In addition, recent research into mechanism of injury and pathophysiology has led to increased biological plausibility for wood dust causation of both cancer and non malignant lung disorders.

Exposure monitoring and protection issues are complicated with wood dust, since there are over 12,000 species of trees worldwide, and a wide range of industrial applications. There are studies which show that biological contaminants, such as fungi and molds, and chemical contaminants, such as formaldehyde, can cause or contribute to the pathology. In addition it seems that different types of wood cause injury through different mechanisms on molecular basis. (Whether that has any major relevance is unclear at this time.)

The US has 34 million asthmatics and 16 million with chronic bronchitis/ chronic obstructive pulmonary disease, with estimated 14 million with COPD undiagnosed. The etiology of these diseases includes genetic predisposition, tobacco smoking and environmental pollutants, in addition to occupational exposures to a wide range of chemicals and dusts. 47 million US citizens have Metabolic Syndrome, characterized by obesity, diabetes, abnormal lipids, and hypertension, and now 24% of the US workforce has Metabolic Syndrome. Obesity is now considered an independent risk factor for lung disease. These figures are all expected to rise over the next 20-30 years.

Because of the history of lung disease findings at higher wood dust exposure levels, with recent lower wood dust dose studies showing no or little adverse effect, and because of the clear carcinogenicity of wood dust vis a vis sino-nasal cancer, and our workforce’s increasing pulmonary risk factors as described above, HEAC support of ACGIH’s position of lowering the PEL to 1 mg/M3 inhalable dust seems reasonable. NIOSH also proposes this level as a REL. A 5 fold reduction in exposure should also reduce the risk of sinonasal cancer to 1 case per million exposed. Many studies, including a recent large US one, show that exposure levels have already decreased well below the current California PEL of 5 mg/M3. .Western Red Cedar is a special case, because of the extensive conclusive scientific analysis of it’s pathophysiology, and should have a PEL of 0.5 mg/M3 and sensitizer designation.

BACKGROUND:

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CHEMICAL AND PHYSICAL PROPERTIES: Wood dust is defined as wood particles resulting from processing or handling of woods. Woods are divided into hardwood, from broad leafed deciduous trees which flower; and softwood, from conifers which do not shed their leaves in the winter. Tropical woods or “exotics”, (which are both ) are frequently a cause of allergic wood dust disease, but are rarely used in the United States.

Chemically, wood is composed of cellulose(a polysaccharide consisting of linear chains of glucose), hemi-celluloses (amorphous heteropolymers, ie matrix polysaccharides, such as arabinoyxlans) and lignin (polymeric phenylpropane), plus hundreds of high and low molecular weight compounds which protect the wood from attack by fungi, insects etc. These include terpenes, stibenes , tannins, flavinoids, quinines, and phenols. In addition, wood can be contaminated by fungi, molds, & insects, which can be irritants or allergenic in their own right. ACGIH notes that 5% to 30% of the wood mass can be composed of these other compounds, and a recent study from Tulane found even higher values for non wood solids.

Wood is often treated with a variety of toxic chemicals including copper, arsenic, chromate copper arsenate (CCA), ammoniacal copper arsenate (ACA), and formaldehyde and pentachlophenol as preservatives; lead based paint in the past; and epoxy and other glues in production of pulp/wood fiber products and plywood, etc.

Western red cedar is a softwood widely used in construction because of its resistance to molds, fungi and other causes of decay. California has only isolated strands of this wood along the coast from HumboldtCounty northward, and imports it from other states and Canada

FORMS, USES AND APPPLICATIONS: Rough cutting operations which “shatter” the wood, generate larger particles (20-30 um or more) which are much less likely to be inhaled into the lungs, but may impact the nasal and sinus mucosa. . Other processes such as sanding, generate smaller particles (1-2 um). Processes which produce smaller particles are also more likely to be indoors, increasing the risk. The type of operation being performed is the most important factor in exposure.

CURRENT WORKPLACE LIMITS AND PUBLIC HEALTH LIMITS: (Usually measured as “inhalable” particulate mass because of effects on both upper and lower respiratory systems)

Cal OSHA : current—Wood dust 5 mg/m3

Carcinogenicity: Not designated by Cal OSHA, but OEEHA recently added it to Prop 65

Fed OSHA: Currently wood dust is regulated as Particulate NOS, (“nuisance dust”) at 15 mg/M3 (CFR 29 1910 1000 Table TZ1

ACGIH 2005 & 2010: TLV-TWA 1 mg/M3 inhalable particulate mass –all species except WRC for which the proposed TLV –TWA is 0.5 mg/M3, and Sensitizer designation.

NIOSH REL

The National Institute for Occupational Safety and Health (NIOSH) has established a recommended exposure limit (REL) for wood dust, all soft and hardwoods, except western red cedar of 1 mg/M3) as a TWA for up to a 10-hour workday and a 40-hour workweek [NIOSH 1992]. This was reviewed and reissued 7/09.

ACGIH Carcinogenicity:A1-Confirmed human carcinogen: oak, beech

A2-Suspected human carcinogen: birch, mahogany, teak, & walnut

A4: Not classifiable as a human carcinogen: all other wood dusts, including Western Red Cedar

International levels: European Union 5 mg/M3

Sweden OEL 2 mg/M3

MAJOR COMERCIAL USES: Construction, furniture and cabinet making, sawmills, carpentry. Outdoor construction projects involve more air moving and larger dust particles generated than indoor furniture making & cabinetry. Industry description: “Companies that cultivate and/or manufacture timber, mill lumber, wood, and/or wood products for construction.” Major changes in industry in recent decades due to increased environmental regulation include use of smaller trees and manufacturing of wood fiber boards instead of planed wood and plywood for construction. An industry document indicates over 90% of the timber in USA is on private land.

HEALTH ENDPOINTS:

ASTHMA/ALLERGIC UPPER AIRWAY DISEASE: The pathophysiologic mechanism linking wood dust to allergic asthma is unclear, although it has been identified quite elegantly for Western Red Cedar. Some studies have shown allergic effects of other woods, and these are equivocal for pine, but aside for WRC, most cases involve exotic tropical woods not native to US or widely used here.

NON-ALLERGIC PULMONARY DISEASE:Chronic non allergic pulmonary disease is the most prevalent health effect, with numerous studies showing increased symptoms of chronic bronchitis or chronic obstructive pulmonary disease (COPD), and/or decrements in pulmonary function. There are numerous other criticisms of the studies, including small numbers, single industrial focus, exposure data obtained by old methods, soft end points and loss to follow-up, etc. Generally, an irritant effect is postulated, due to wood dust itself, and/or contaminants

CANCER ENDPOINT: The mechanism of carcinogenicity unclear, but new research demonstrates specific mutations .The focus is on sinonasal cancer, both adeno and squamous. Laryngeal cancer andlung cancer are also of concern, but there is much less evidence for these.

OTHER LUNG DISORDERS: Alveolitis, hypersensitivity pneumonitis, and pulmonary fibrosis have all been reported associated with wood dust exposure, but may be actually due to fungi and molds involved in processing.

DERMATITIS: Wood dust can cause both Type I and Type IV hypersensitivity skin reactions as well as irritant dermatitis.

REVIEW: MECHANISM OF PATHPOPHYSIOLOGY FOR WOOD DUST RELATED DISORDERS

The basic primary mechanism for all wood dust related diseases is presumed to be an initial irritant effect of the wood dust on the tissue cells. In 2009,Pylkkanen et al in Finland used dust from dried pine, birch and oak, generating dusts with 90% less than 5 um, and exposed human bronchial epithelial cells from The American Type Culture Collection in 3 concentrations (10, 50, &500um/ml) and 5 duration periods from 0.5-24hr. All wood dusts caused cytotoxicity, dose dependant and statistically significant at 2 & 6 hrs compared with controls. Exposure to all three woods stimulated reactive oxygen species (ROS) and induced capase-3 protease activity. Maata et al studied wood dust particle induced pulmonary inflammation in mice to identify the mechanisms by which lung diseases develop. They used aged oak and birch, created fine dusts with 90 % 5um or less, and used titanium dioxide as a control dust. They instilled the dusts intranasally 2 xs week for 3 weeks. Airway hyper reactivity to methacholine was measured by body plethysmography. The mice were then killed and blood, bronchial alveolar lavage fluids, and tissue samples were taken. The results showed that repeated exposure to the oak and birch dusts caused influx of inflammatory cells into the lungs, and on a molecular level was associated with the increase in several cytokines, chemokines and chemokine receptors in the lung tissue.

Attempts at identifying an IgE mediated allergic mechanism have not been successful for woods used in the United States. Studies show elevated levels in some Pts with clear allergic asthma reactions to wood dust, but not others, and only in small numbers. The actual chemical agent responsible for Western Red Cedar related asthma has been identified as Plicatic acid, a component of both Western & Eastern cedars.

Most of what we now know about carcinogenesis has been discovered since the 1970s. With the development of our ability to look at specific changes to parts of the genome. In the past 5 years, there has been major work looking at the mechanism of wood dust and carcinogenesis. In brief, it is believed that 5-10 sequential mutations are required to transform a normal cell into a cancer cell. (See attached diagram from the latest edition of Harrison’s internal medicine text).

Another significant mutation is inactivation of the tumor suppression gene P53 . Several studies have investigated this recently. Homila et al found a high prevalence of TP53 mutations in a large group of samples from 358 sinonasal cancers with data on occupational exposure , and found the mutation levels significantly elevated with duration of exposure 24 years (OR 3.5, 96%CI 1.2-10.7). In a further experiment, they reported the actual sequence change for 159 of the TP53 mutations, identifying C-T transitions, base changes in the coding region, G-T transversions and identified the actual codons most frequently affected .

REVIEW: NON-ALLERGIC PULMONARY DISEASE

Overwhelmingly studies looking at health effects of wood dust exposure describe non allergic pulmonary effects rather than immunologically mediated problems such as asthma or alveolitis. The mechanism by which these effects are produced is thought to be an irritant effect causing an inflammatory reaction which leads to chronic bronchitis (chronic cough and mucus production without PFT changes) and chronic obstructive pulmonary disease (COPD) which includes cough, mucus production and non reversible obstructive PFT changes.

The ACGIH TLV document critically reviewed studies of chronic non allergic pulmonary disease in development of its proposed TLV of 1 mg/M3, presented in 2005, and reissued in 2010 (although reissued without an updated literature review). Glindmeyer et al (2008) is clearly the most comprehensive analysis published to date, following a cohort of employees in ten different wood processing plants over a 5year period, with exposure data and medical surveillance, including spirometry. The exposure data was presented in several formats, including the standard inhalable dust used in most studies previously, but also with respirable fraction broken out, because of their focus on pulmonary disorders. The authors also analyzed the exposure data by separating wood solids from the non wood fraction of the dusts (volatiles, water, fungi, etc). Spirometry was performed according to ATS standards and equipment was calibrated and maintained appropriately. Measurements were compared to a very large data base of Caucasian and African-American workers from the US who were non smokers and not exposed to pulmonary hazards on the job.

This study was initiated, according to the authors, because of criticisms of previous studies described above. The exposure assessment revealed geometric mean values of personal inhalable dust samples ranging from 0.82 to 2.51 mg/M3 across the ten plants, with geometric standard deviations ranging from 2.1-2.8 mg/M3. The respirable dust fraction was 0.10-0.23 mg/M3 with geometric standard deviation in the range of 2.0-3.5. Their conclusion was “Exposure response analysis showed no statistically significant adverse respiratory effects to any wood solids fraction”. However separating out the wood dust solids from other wood components such as terpenes, and possible contaminants such as fungi, may be removing the actual cause of disease in different wood processing operations. If fungi in sawmills or chemicals such as glues in plywood manufacturing operations are part of the etiology for lung diseases seen in those industries, calculating disease rates based on their removal is artificial unless one postulates new control mechanisms for that part of the hazard. In addition, the inhalable wood dust exposures were, for the most part, lower than the current PEL which is 5 mg/M3 This might support the concept that lowering the exposure decreases disease incidence. Finally a significant part of their original cohort was lost to medical follow-up, which also raises questions about the conclusions, and it does not appear that the PFT measurements were taken on the same shift as the personal dust sampling.

Mandryk et al (1999) in Australia studied the effectsof wood dust exposure on cross shift PFTs and symptoms. Dust exposure was monitored by personal sampling for both inhalable and respirable dust. Geometric means for inhalable dust were in the range generally below 5 mg/M3. (At the time of the study the Australian OEL was 5 mg/M3 for softwoods and 1 mg/M3 for hardwood). PFT measurement equipment and methods were described and were academically appropriate, and lung function cross shift measurements and personal dust sampling were done on the same shift. The study also evaluated the effects of fungi/endotoxin levels) and found in sawmills the biologicals levels are higher as might be expected.

Andersen et al (1977) studied mucostasis in relation to exposure level because of elevation of woodworkers among those with nasal cancer in Denmark where the study was done. Whitehead summarizes Andersen as showing that “mucostasis drops to the background (control) level only in the lowest exposure group which had a mean exposure level of 2.2. mg/M3. Andersen appears to show a clear dose-response relationship between exposure level and mucostasis, which is postulated as a risk factor for sinonasal cancer. Andersen’s work was cited by Whitehead (1982) in a review article as being one of the two studies having “the soundest evidence” for his recommended TLV of 2 mg/M3 total dust at that time.

Chan-Yeung et al (1980) concludes that TLV of 5 mg/M3 is too high, but it’s less clear on suggesting a quantitative alternative level, partly because the overall exposure levels are fairly low since they were looking at pulp and paper mills in British Columbia rather than furniture making or other woodworking where dust exposure levels are generally higher.