# Presentation: 844782

## Research Goal 4: Contribute to Reductions in Hearing Loss through the Understanding of Causative Mechanisms

-  Rickie R. Davis, Ph.D.
- Commander, U.S.  Public Health Service
- Division of Applied Research and Technology

## Objective

- “How does basic research help achieve the HLR program mission?”

**Notes:**
The objective in presenting this talk is to review the role of basic research in the hearing loss research program.

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
Although not all inclusive I’m going to talk about the six organizing areas the hearing loss research program has worked in for the past 10 years or so.

These are:
	Surveillance
	Normative databases
	Impulsive noise
	Aging
	Genetics of susceptibility to noise
	and Ototoxic chemicals

These are the subsections of Chapter 6 in your briefing book.

## Surveillance

- “[No one] can effectively prevent or control disease without knowledge of when, where, and under what conditions cases are occurring” MMWR
- There currently is no national surveillance program for occupational hearing loss or noise exposure

**Notes:**
What is surveillance? In the public health model it is a continuous process of systematic collection, analysis, interpretation and dissemination of descriptive information for monitoring health problems.  This feeds back into the regulatory system which leads to changes in public policy.

Currently there exists no national surveillance program for occupational hearing loss, nor for monitoring noise exposure or levels in industry.

HLR program has recognized the need for data for years. 1988 Top Ten. 1996 Practical Guide. 1996 NORA document.  The Hearing Loss Research Program has made some efforts over the past 10 years or so to fill some gaps in surveillance.

## Michigan is the only state collecting these data
SENSOR – cooperative agreement
Michigan SENSOR Program (1992-2000, 2002-present)
Reports from employers, audiologists and otolaryngologists
Represents new cases

- SENSOR – cooperative agreement
- Michigan SENSOR Program (1992-2000, 2002-present)
- Reports from employers, audiologists and otolaryngologists
- Represents new cases

- Surveillance Support

**Notes:**
NIOSH has a program to fund states to collect sentinel occupational events: SENSOR. Sentinel Event Notification Systems for Occupational Risk.

Of the current cooperative agreements, Michigan is the only state collection noise-induced hearing loss data.  These data are reported by employers with hearing loss prevention programs, audiologists and otolaryngologists.

Program initiated by NIOSH through states’ department of health.

## Michigan SENSOR Program

**Notes:**
This is an example of the information available from the Michigan SENSOR program.  As you can see there has been an increase in reports through the first ten years.

This is a scan of a page out of Michigan’s 2001 report.  What it shows is new cases of noise-induced hearing loss.  After 1993 it appears that the number of cases reported every year asymptote but an interesting change happens in that the number of cases reported by industry decreases and the number of cases reported by health professionals increases.  Another interesting observation is that the researchers estimate that in Michigan in 1996 there were an estimated 208,573 workers exposed to noise.  So somewhere between 0.8% and 1% are having a large enough hearing loss to be flagged by their hearing loss prevention program or by a health care professional.

Of course there are noisy workplaces which don’t have hearing loss prevention programs.

## Facilitating our Partners

- OSHA 300 Log
- What’s ahead?
- Database activity
- National Exposure at Work Survey

**Notes:**
OSHA originally published guidelines for reporting occupational illness and injuries in 1971
One purpose of these regulations was to produce national statistics for work-related illness and injury
However, the requirements for recording noise-induced hearing losses were ambiguous and insufficient to accomplish this.
There were three main problems:
   a)  the definition of hearing threshold shift was too large to be useful in identifying many noise-induced hearing losses
   b)  state OSHAs could use different definitions of threshold shift in their recordability regulations
   c)  hearing loss was lumped together with other repetitive trauma illnesses so that hearing loss could not be tracked as an individual outcome

When OSHA proposed revising its rule for recording and reporting occupational illnesses and injuries in 1996, the HLR program recognized an opportunity to help formulate a system for recording noise-induced hearing threshold shifts that would allow surveillance of occupational hearing loss.

The HLR program:
   a)  provided OSHA with an extensive analysis of various definitions of threshold shift in order to develop a useful definition
   b)  showed that rates of threshold shift were high enough to warrant a dedicated column for recording hearing loss

OSHA adopted all the HLR program recommendations with only minor changes
The final OSHA recordability rule became effective January 1, 2004.
Initial rates of noise-induced threshold shift for calendar year 2004 should be available from the Bureau of Labor Statistics very soon

The OSHA 300 log will provide national data on the incidence of occupational threshold shift that can be tracked annually by employer demographics (e.g., industry, company size, etc.).  This will help focus prevention efforts.

Michigan SENSOR and the OSHA 300 log give us numerator data (how many cases) but we still need denominator data (how many exposed).  NEWS should eventually provide the denominator data.

NEWS will update the NOES data, which is now over 20 years old

NEWS is being accomplished sector by sector; currently, it is in pilot-testing for the first sector it will survey

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
Next we are going to talk about normative databases.

## Need for Baseline Data

- Normal baseline for comparison
- General population vs. non-exposed
- Currently old data
- Collected in the 1980’s
- Self-reported
- Not nationally representative

**Notes:**
Two types of comparison data are necessary:  general population data and non-exposed population data

Previously, comparison data on hearing loss in the general population was either:
     30 or 40 years old
or, based on self-report rather than audiometric testing

Comparison data from non-exposed populations was either:
     30 or 40 years old
&,  not nationally-representative

## National Health and Nutrition Examination Survey

- NHANES has not tested working age group every year
- 1960-62; 1971-75
- 1999-2004
-  Active partners

**Notes:**
Nationally-representative surveys of hearing ability are expensive and labor intensive
The National Health and Nutrition EXAMINATION Survey conducted by the National Center for Health Statistics provides a vehicle for it.
Working age adults were tested through NHANES in 1960-1962 and 1971-1975 but not since

Largely through HLR program lobbying, audiometric testing in adults aged 20-69 was included in the six-year survey cycle from 1999-2004

The survey includes data on occupational and non-occupational exposures, so it will be possible to construct a contemporary non-exposed reference database

The HLR program managed ALL the technical aspects of the NHANES audiometric testing component – protocol & questionnaire development, technician training, oversight of data collection, data QA procedures, and analysis

Beginning in 2005, NHANES is conducting hearing testing in youth aged 12-19 (which will provide data on hearing levels in workers just entering employment) and 70+ (which will provide data on older workers who are becoming a larger part of the workforce).

- Age categories:

- 20-29
- 30-39
- 40-49
- 50-59
- 60-69

**Full Sample**

**Non-Noise Exposed**

**Notes:**
Here is an example of the normative data based on 1999 and 2000 data available through our collaboration with NHANES.  

Left ears of the total sample and a subsample of non-exposed subjects.  Noise appears to play an important role until about age 40 when aging appears to become a bigger contributor.

Noise exposure has a definite effect on thresholds in the older categories.  There is a noise notch at 6 kHz even in the non-noise exposed subgroup.  This could mean:
	Even those who do not believe they have significant noise exposure are affected by day to day noise or
	The reference value for audiometric zero at 6kHz is incorrect, which some studies have suggested.

## The Age, Gene/Environment Susceptibility Study (AGES) 

- Icelandic Heart Association Research Institute requested technical assistance
- 10,000 individuals, 67 or older
- Use DNA information to locate genes of interest
- Role: technician training, consulting

**Notes:**
As an adjunct of the NHANES effort, the HLR program was invited to participate in the Icelandic Age, Gene/Environment Susceptibility Study.  The Icelandic Heart Association Research Institute has a long-term study of aged individuals.  There are currently more than 10,000 individuals age 67 or older.  Will be using DNA testing to isolate genes of interest in this population.  The role of the HLR program is to consult on protocol development and train technicians.  They are using the NHANES protocols.

The benefit to hearing science is the possibility of discovering genes in the human population making them more or less susceptible to aging or noise.

HLR program role: Technician training, consulting on audiometric testing.

## Fels Longitudinal Study

- Wright State University, started in 1929
- 1979-1983 collected hearing and noise exposure levels
- Genetics
- Role:
- Involved in getting audiometry restarted, training techs, calibration
- Analysis of data
- Audiometric Data Available 2007

**Notes:**
Along similar lines, the Fels Longitudinal Study, currently being managed by the Wright State University School of Medicine, was started in 1929.  It is the longest running study of development in the world.  Currently individuals who are great-grandchildren of the original participants.  In the period 1979 to 1983 they collected noise exposure levels and hearing levels.  
In 2004 Fels approached the HLR program about the possibility of re-starting collecting hearing threshold data.  We were able to help them in this effort by loaning them equipment, training technicians, helping resolve calibration issues.  The Hearing Loss Research program will be involved in analyzing the hearing loss data as soon as it becomes available in 2007.

## ANSI S18.12/Royster Database

- Made public from funding by HLR program
- 22 hearing conservation databases
- 15,000 employees –at least 4 audiograms
- 3,000 employees with 8 audiograms
- Including “good” programs and non-exposed populations
- Provided to MRC of the UK for their age-noise analysis

**Notes:**
In the mid-1980’s the ANSI S18.12 committee attempted to develop software which would categorize a hearing loss prevention program as good or bad based on a number of criteria.  This effort was facilitated by the HLR Program making a tape of reference audiometric databases publicly available.  This tape consists of 22 databases with 15,000 employees having at least 4 serial audiograms and 3000 employees having 8 or more audiograms.  The tape included audiograms from companies which the Roysters classified as “good” programs (the workers wore hearing protection 100% of the time in noise) and workers in non-exposed populations.

The HLR program has used these databases a number of times as reference databases for exploring different techniques for analyzing program data.

These files have been provided to the Medical Research Council of Great Britain for their efforts in quantifying aging and noise.

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
I would now like to talk about impulsive noise.

## Impulsive Noise

- Impulsive noise more damaging than continuous noise of same energy
- Shown in numerous animal studies
- NIOSH study in Ford stamping plant
- Law enforcement, military and manufacturing

**Notes:**
We have known for a number of years that impulsive noise is more damaging to the ear than continuous noise of the same energy.  This has been shown in both animal studies and human studies.  For example, Dunn et al exposed one group of chinchillas to impact noise and a second group to continuous noise controlling for energy and spectrum.  They found that the chinchillas exposed to impact noise had a greater threshold shift than the chinchillas exposed to continuous noise.  In a study with Ford the HLR program found that workers in the stamping plant had more hearing loss than workers in the assembly plant even though they were exposed to about the same level of noise.  The stamping plant had an impulsive component.

Industries where impulsive noise is common are law enforcement, where workers are required to qualify on firearms once or more times per year, military, where they may be exposed to gunfire as well as engage in target practice, and manufacturing, including stamping, bottling, printing.

## Industrial Dosimeters

- No dosimeter currently exists which can incorporate impulsive noise of greater than 145 dB SPL
- No current damage risk criteria exist for impulsive noise

**Notes:**
One of the areas in impact noise where the HLR program has had products is in the area of industrial dosimeters.  It is common practice for the head of the hearing loss prevention program to put a noise dosimeter on a worker to get a measure of their noise exposure for the day.  The HLR program has found that this basic tool is not well qualified for this effort if the impulsive noises are greater than 140 dB SPL.  Because current regulations prevent exposure to any impulsive noise greater than 140 dB SPL, dosimeter manufacturers do not design for impulsive noises greater than that.  Note on the graph how a gun shot is peak clipped by the dosimeter.  In addition, this value is not incorporated into the Leq (integrated equivalent level) by the dosimeter, leading to a false dose for the worker.

However, we don’t currently have damage risk criteria for impulsive noise.  In order to develop these criteria, the proper tools must be developed.  This is a current HLR program effort.

## From Kardous

**Notes:**
Note clipping of gunshots.  Note underestimate of dose.

## Cooperative Partnerships for Impulse Noise Research

- Early Animal Work
- Grants to academia
- CRADA with Larson-Davis
- United Brotherhood of Carpenters

**Notes:**
In the 1980’s NIOSH conducted a series of chinchilla studies looking at the effects of impulsive noise on hearing.

The HLR program has been involved by providing grant funding to various impulsive noise researchers.  Dr. Don Henderson has been involved in many studies over 25 years looking at the effects on the ear of impulsive noise.  Dr. Roger Hamernik has been involved in looking at the effects on the ear but also developing strategies for analyzing impulsive noise signatures to determine a damage hierarchy.  A more recent partner is Dr. Jay Kim who has been involved in the earlier work we talked about at the University of Cincinnati, but who is now applying second generation signal processing techniques—analytical wavelet transforms—to impulsive noises.

In addition we have a CRADA—Cooperative Research and Development Agreement with Larson-Davis, one of the largest dosimeter and noise measurement companies in the world, to develop a noise dosimeter which correctly measures and integrates impulsive noise into a daily dose measurement.

The United Brotherhood of Carpenters training facility in Ohio will be testing a hearing protector which was developed by the French and German Army to allow communication while filtering out impulsive noise.  The HLR program proposed this to answer the concern about hearing warning signals and communication.  This will be the largest civilian pilot of these specialized hearing protectors yet.

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
I would next like to talk about the aging component of hearing loss and its interaction with noise.

## Age-related Hearing Loss

- An important role of the NHANES database, Fels study, AGES study
- Better understanding of age-related hearing loss
- Requires long-term commitment, by definition

**Notes:**
It is generally believed that the average person will lose their hearing as they age.  This may or may not be true. Age-related hearing loss has a characteristic of beginning in the high frequencies and progressing to lower frequencies as the person ages.

The three normative studies I discussed earlier will provide important information: NHANES will allow for a cross-sectional view of age-related hearing loss in the general population, Fels will allow for a lifetime longitudinal study of aging in individuals and the AGES study may allow identification of genes responsible for aging in humans.

These studies require a long-term commitment to obtain valid data.  Can’t turn these studies off and on.  Also requires a commitment on the part of the subjects.

## Does noise interact with age?

**Notes:**
One of the big questions is how do noise and aging interact.  In the past the assumption has been that the effects of aging are simply subtracted from the hearing loss to arrive at a “true” threshold shift.  Franks and Davis did this using the Royster-ANSI databases.  These are audiograms derived from hearing conservation programs in the US and Canada.  

ANSI database shows that subtraction of aging resulted in loss of ability to detect early hearing loss

The expert system software was run on the databases to remove any spurious audiograms.  The result was the two white curves showing an increase in threshold with aging.  If the standard aging parameters are applied to the curves, the two red curves are generated.  This shows that threshold actually gets better with age.  By age correcting the audiograms, the hearing conservationist is losing the resolution to detect small threshold shifts and intervening to save worker hearing.

## Once a hair cell is lost, it cannot be lost again

- C57BL/6J mice
- Show early presbycusis
- Hearing loss “caught up” in control mice to level of exposed mice

- Erway et al, 1996

**Notes:**
In a similar study in mice we showed that mice exposed one time to noise did not show any age related hearing loss until about 2 months later, while their unexposed controls showed hearing loss all along.  This would argue that aging and noise-induced hearing loss are not additive.  Once a hair cell is lost, it cannot be lost again.

- Attempted to modify age-related hearing loss in prematurely aging mice by administering a ROS inhibitor
- Did not significantly modify age-related hearing loss

- Davis et al, 2005

**Notes:**
In this study we attempted to protect hearing in mice who show accelerated presbycusis.  We administered the free radical scavenger N-acetyl-L-cysteine to mice in their drinking water for 6 months.  They were tested monthly for the ability to generate the auditory brainstem response.  At the end of the experiment there was no difference between the group receiving NAC and the group receiving regular water.

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
I’d next like to talk about genetics in susceptibility to NIHL.

## A single gene can modulate susceptibility to NIHL

- Threshold shift vs. exposure level
- Not only differs in susceptibility but also probably mechanism
- Certain number of workers will sustain a hearing loss

- Davis et al, 1999

**Notes:**
This experiment was conducted in collaboration with the University of Cincinnati Department of Biological Sciences.  Our interest was to quantify the difference in susceptibility between C57BL/6J (B6) mice and CBA/CaJ mice.  Groups of mice were exposed to broadband noise at different levels, allowed to recover for 9 days and tested for the ability to generate the auditory brainstem response at different frequencies.  What we found is that not only did the two strains differ based on sensitivity to noise, but the slopes of the two functions differed significantly.  This seemed to indicate that the mechanisms of damage probably differed also.  The steep slope of the CBA indicates that it is probably necrosis or mechanical damage of the inner ear which is occurring, while the shallower slope of the B6 indicates that the ear is probably being damaged physiologically.  Curve on left is B6, curve on rt is CBA. 

Certain number of workers will sustain a hearing loss.  May be genetically related.

NIOSH Role: partner with academia.

## Six Areas of Research

- Surveillance
- Databases
- Impulsive noise
- Aging
- Genetic susceptibility
- Ototoxic chemicals

**Notes:**
Finally, ototoxic chemicals alone and in combination with noise.

## Certain chemicals damage hearing alone or in combination with noise
Shown in workers and animals
Solvents, heavy metals, asphyxiants and pesticides

- December 6, 2005

- Certain chemicals damage hearing alone or in combination with noise
- Shown in workers and animals
- Solvents, heavy metals, asphyxiants and pesticides

**Notes:**
The last topic I’d like to talk about is ototoxic chemicals either alone or in combination with noise.

An interesting speculation comes out of some recent work that Argonne National Labs released recently.  Looking at hairs from Beethoven they found that he may have died from high lead levels.  It is interesting to speculate that he also may have been suffering from a chemically induce deafness due to lead poisoning.

Certain chemicals have been shown in workers and in experimental animals to produce hearing loss.  These chemicals are the solvents, heavy metals (such as Beethoven’s lead) and asphyxiants (such as carbon monoxide).

## Long-term effort

- International Collaborations
- Researchers in England, Sweden, Finland, Poland, Denmark, Colombia, France and Brazil
- Intramural Efforts
- Grants
- HHEs

**Notes:**
HLR program has been involved in this research for many years

This has been a long-term effort.  Morata conducted her dissertation in conjunction with NIOSH in 1990 while a graduate student at the University of Cincinnati.  A number of international collaborations have been generated by this research including researchers in the United States, England, Sweden, Finland, Poland, Denmark, Colombia, France and Brazil.

Intramural efforts and HHE’s have been conducted by HLR program researchers.  Grants have been provided to Yale, Loma Linda University, SUNY Buffalo and others to work on this topic.

## Intermediate Outcomes of these efforts

- Involved in developing National and International Regulations
- European Union, Australia/New Zealand and Brazil
- Department of Defense
- American Conference of Governmental Industrial Hygienists
- American College of Occupational and Environmental Medicine

**Notes:**
Products of these efforts have resulted in changes in regulations (outputs).  The European Union has issued a 2003 European Parliament Directive EC 10 which states, under “Obligations of Employers” that when carrying out risk assessments, employers should “...give particular attention to: any effects on workers’ health and safety resulting from interactions between noise and work-related ototoxic substances... ” 

The U.S. Army Fact Sheet on “Occupational Ototoxins and Hearing Loss.” This fact sheet recommends yearly audiograms for workers whose chemical exposures are at 50% of the most stringent criteria for occupational exposure limits, regardless of the noise level. 
Legislation regarding worker compensation has also changed in Australia and Brazil. 

The HLR program helped prepare best practice guidelines by external groups. The American Conference of Governmental Industrial Hygienists note in its Noise Section: “In settings where exposure to toluene, lead, manganese, or n-butyl alcohol occurs, periodic audiograms are advised and should be carefully reviewed.” 

## Collaborations and Partners

- Government agencies
- OSHA, MSHA
- Industry
- General Motors, Ford, UAW, JAA
- Larson-Davis
- United Brotherhood of Carpenters

- Universities and Academia
- Univ. of Cincinnati (Biology, M.E., Comm.)
- Yale
- SUNY Plattsburgh & Buffalo
- University of Washington
- Wright State University

**Notes:**
In the causative mechanisms arena we have had a number of partners and collaborators.  Government agencies have provided resources and encouragement to work on certain problems.

Universities and Academics have been very valuable as collaborators.  Faculty at the University of Cincinnati in Biological Sciences, Mechanical Engineering and Communication Sciences and Disorders have collaborated on a number of activities.  Each of these departments have provided graduate students to either work on problems or produce theses and dissertations with members of the program.  Yale, SUNY, and UW are NIOSH grantees.  Wright State has utilized us as a resource for the Fels survey.

In industry we have partnered with General Motors, Ford, the United Auto Workers and James Anderson and Associates on a number of activities and projects.

Larsen-Davis has signed a CRADA with us to develop an impulse meter.

United Brotherhood of Carpenters has been issuing a specialized hearing protector developed to be effective against impulse noise while allowing for good communication.

## Citation Analysis

- 75 times Morata et al., 1993
- 47 times Erway et al., 1996
- 37 times Morata et al., 1997
- 36 times Morata et al., 1994
- 14 others cited 3 or more times

**Notes:**
An article being cited by a peer is a measure of it’s value to the community. Eugene Garfield, founder of ISI which developed Science Citation Index, indicates that the average scientific paper is cited zero times. 

The team has had good luck having their published articles cited by peers. Here are the results of a citation analysis conducted this past fall.

These articles and their citation histories are listed in your briefing book, and PDF’s of the articles will be available on the website we are building.

## Emerging Issues

- Increase in digital technology/cheaper technology
- Surveillance for noise and hearing loss
- NIHL prophylaxis
- Complete human and mouse genome sequence
- Acceptance of noise-chemical interaction

**Notes:**
We see some emerging issues in causative mechanisms.

Increases in digital technology power and lowering of price will make the prospect of an inexpensive impulse meter better.  We are involved in developing such a meter with Larsen Davis.

Surveillance remains a concern.  We plan to remain involved with NHANES (who will be doing hearing tests on age groups which are not generally considered workers), AGES, and Fels.

There is much research in prophylactic chemicals which can be taken before noise exposure.  The DoD is supporting these efforts.  It is not clear that a worker could take such chemicals for 30 or 40 years without side effects.  We are monitoring these efforts.

With the complete decoding of the human and mouse genomes we can now look for sequences that are unique to workers who appear to be more susceptible to NIHL or aging.  It also gives us the opportunity to look for interactions between multiple genes.  We will be monitoring these efforts.

Finally, with the European Union, Australia/New Zealand and DoD accepting the idea that noise and chemicals can interact to augment hearing loss, it seems only a matter of time before other industrialized countries recognize this hazard.

## Acknowledgements

- Chuck Kardous, M.E., P.E.
- Electronic Engineer (impulse noise)
- Thais Morata, Ph.D.
- Audiologist (ototoxic chemicals)
- Christa Themann, M.A.
- Audiologist (surveillance, databases)
- Other members of the HLPT

**Notes:**
I would like to acknowledge the hard work of my fellow Hearing Loss Prevention Team members who worked on the chapter with me.  Chuck Kardous, one of two Electronic Engineers on our team, wrote the section on impulse noise.  Thais Morata, one of five audiologists on our team wrote the section on ototoxic chemicals.  Christi Themann, an audiologist on the team and currently graduate student in epidemiology, wrote the sections on surveillance and databases.  Other members of the team provided great feedback and wrote pieces of the chapter as it came together.